Tricyclic compounds as TXA2 antagonists

ABSTRACT

Novel Tricyclic compound represented by formula ##STR1## possess a TXA 2  biosynthesis inhibiting act and/or a TXA 2  receptor antagonizing activity, and are expected to have preventive and therapeutic effects on ischemic diseases, cerebro-vascular diseases, etc.

This application is a division of application Ser. No. 612,446, filedNov. 14, 1990, now U.S. Pat No. 5,118,701 which is a division ofapplication Ser. No. 368,242, filed Jun. 6, 1989, now U.S. Pat. No.4,999,363.

BACKGROUND OF THE INVENTION

The present invention relates to novel tricyclic compounds whichstrongly antagonize a biological action of thromboxane A₂ (hereafterreferred to as "TXA₂ ") by an inhibitory activity of TXA₂ biosynthesisand/or a TXA₂ receptor antagonizing activity.

It is hitherto known that TXA₂ strongly aggregates platelets and is apotent vasoconstrictor [cf. Arachidoic Acid Cascade and Drubs, edited byShozo Yamamoto, Gendai Iryo Publishing Co., Ltd. (1985)]. Further TXA₂is a powerful vasoconstrictor against bronchus and bronchial smoothmuscle. Therefore, TXA₂ is considered to take part in pathologicalconditions over a wide range. As examples, the following diseases can beexemplified.

(1) Ischemic disease

For example, myocardial infarction, angina pectoris, and thrombosis

(2) Cerebro-vascular disease

For example, transient ischemic attach, migraine, cerebral hemorrhage,and cerebral infarction

(3) Peripheral vascular diseases and disease caused by unbalanced lipid

For example, atherosclerosis, capillary convulsion, peripheralcirculation disorders, hypertension, pulmonary embolism

(4) Inflammatory and allergic diseases

For example, bronchial asthma, bronchitis, pneumonia, nephritis, andhepatitis

(5) Shock

(6) Cancer metastasis.

Accordingly, compounds that antagonize the action of TXA₂ (compoundshaving an inhibitory action of TXA₂ biosynthesis and/or a TXA₂ receptorantagonizing action) are expected to have therapeutic effects inpreventing or treating optional one or more of the diseases describedabove or other diseases in which the action of TXA₂ is desirablyprevented. Further where, in drugs used for medical purposes heretofore,application thereof is limited due to side effects medicated by TXA₂ orconsidered to be mediated by TXA₂, it is expected to alleviate the sideeffects by the use of compounds which antagonize the action of TXA₂.

As inhibitors against biosynthesis of TXA₂, representative compounds areexemplified in Journal of Organic Synthesis Chemistry, 45, 2 (1987). Inaddition, compounds having the following structures can be illustrated.##STR2##

The compounds contain a pyridine or imidazole partial structure andcarboxyl therein and it is known that these functional groups areimportant for developing the action.

On the other hand, as an antagonist of TXA₂, representative compoundsare exemplified in Thrombosis Research, 44, 377 (1986).

Furthermore, an indole compound having the following structure: ##STR3##and the like are disclosed in Japanese Published Unexamined PatentApplication No. 249960/1986 [West German Patent Application (DE) No.3,514,696] and a compound having the following structure: ##STR4## andthe like are disclosed in Japanese Published Unexamined PatentApplication No. 212552/1986 [DE 3,508,692]. These compounds are allderivatives having a phenylsulfonamide group and exhibit an activity ofantagonizing TXA₂.

Furthermore, there is reported a finding on the enhanced orcomplementary effect of the two activities by the use of TXA₂biosynthesis inhibitors and TXA₂ receptor antagonists in combination[Eur. J. Pharmacol., 85, 331 (1982)].

There is also a report on compounds having both TXA₂ biosynthesisinhibitory action and TXA₂ receptor antagonizing action [Thromb.Haemostasis, 58, 664 (1987), etc.].

In tricyclic compounds in association with the present invention whichare represented by the following formula (II): ##STR5## oxepinederivatives (wherein X^(A) --X^(B) is --CH₂ O--) having carboxyl or aderivative thereof (for example, an ester, an amide, etc.; hereaftercollectively referred to as a carboxylic acid group) as a substituent(X^(C)) on the benzene ring wherein the 11-position (X^(D)) isunsubstituted or has various substituents such as oxo (═O), methylene(═CH₂), alkoxy, etc. are known as showing antiinflammatory andantiallergic activities, and the like [J. Med. Chem., 19, 941 (1976);ibid., 20, 1499 (1977); ibid, 21, 633 (1978); U.S. Pat. No. 4,282,365(Japanese Published Unexamined Patent Application No. 21679/1983); U.S.Pat. No. 4,585,788, Japanese Published Unexamined Patent ApplicationNos. 152673/1986, 152674/1986 and 152675/1986].

There are also known oxepine derivatives showing antiasthmic andantiallergic activities, etc. wherein X^(C) is unsubstituted or has asubstituent other than the carboxylic acid group, for example, alkyl,alkoxy, halogen, etc. and X^(D) has an alkylene chain substituted at theterminal thereof with alkylamino via hetero atom (--NH--, --O--, --S--,etc.), methine (═CH--), imino (═N--), etc. [Japanese PublishedUnexamined Patent Application Nos. 126883/1983 (EP 0085870A),227879/1984 and 152669/1986; U.S. Pat. Nos. 3,354,155 and 3,420,851].Furthermore, oxepine derivatives wherein X^(D) contains phenyl or, analicyclic or aromatic heterocyclic group at the terminal thereof via--NH-- are known to show anticholinergic and antihistaminic activities,etc. [Japanese Published Unexamined Patent Application Nos. 150083/1981(U.S. Pat. Nos. 4,396,550 and 4,465,835), and 139073/1982]. As theheterocyclic rings, piperazine, piperidine, morpholine, pyrrolidine,quinuclidine, pyridine, benzodioxane, indole and quinone areillustrated. Furthermore, cycloheptene derivatives (X^(A) --X^(B) is--CH═CH--) or thiepine derivatives (X^(A) --X.sup. B is --CH₂ S--)wherein X^(D) contains at the terminal thereof an alicyclic saturatednitrogen-containing heterocyclic group, for example, piperazine, via--CONH-- are known to show a calcium antagonizing activity [JapanesePublished Unexamined Patent Application Nos. 47466/1986 (U.S. Pat. No.4,749,703) and 153280/1987]. Furthermore, doxepin derivatives [X^(A)--X^(B) is --CH₂ O--; Drugs, 13, 161 (1977) ] or dothiepin derivativesX^(A) --X^(B) is --CH₂ S--; Arz.-Forsch., 13, 1039 (1963), ibid., 14,100 (1964) ] wherein X^(C) is hydrogen and X^(D) hasdimethylaminoisopropylidene as its substituent are known to show anantidepressive action.

Furthermore, oxepine derivatives having an anti-allergic activitywherein X^(C) has the carboxylic acid group and X^(D) has an alkylenechain substituted at the terminal thereof with alkylamino via a heteroatom, or its 11-position is directly bound to an alicyclic saturatedheterocyclic ring such as piperazine or homopiperazine, etc. are known[Japanese Published Unexamined Patent Application Nos. 28972/1985 (U.S.Pat. No. 4,596,804), 152670/1986, 152671/1986, 152672/1986, 152676/1986,257981/1986 and 17877/1988]. Likewise, there are known compounds havingan imidazole ring directly bound to its 11-position [Japanese PublishedUnexamined Patent Application No. 21679/1983 (U.S. Pat. No. 4,282,365)].These are also disclosed oxepine or cycloheptene [X^(A) --X^(B) is --CH₂CH₂ --] derivatives showing an antihistaminic activity wherein X^(D) isalkylaminoalkylidene [Japanese Published Unexamined Patent ApplicationNo. 45557/1987 (British Patent No. 8,520,662)]. Furthermore, there aredisclosed oxepine derivatives showing antiallergic an antiinflammatoryactivities, etc. wherein X^(D) contains at the terminal thereofalkylamino or alicyclic saturated nitrogen-containing heterocyclic groupvia methine, methylene or imino (Japanese Published Unexamined PatentApplication No. 10784/1988). As the heterocyclic groups,4-methylpiperazine, 4-methylhomopiperazine, piperidine, pyrrolidine,thiomorpholine and morpholine are exemplified.

Novel and useful TXA₂ antagonists (drugs having the TXA₂ biosynthesisinhibitory activity and/or TXA₂ receptor antagonizing activity) areexpected to have preventive and therapeutic effects on various diseases,and are in demand.

SUMMARY OF THE INVENTION

An object of the present invention is to provide novel tricycliccompounds having, as the substituents, both an aromatic cyclic groupsuch as aromatic hydrocarbon or aromatic heterocyclic group, etc. andcarboxyl or its esters on the side chain thereof, which can prevent theaction of TXA₂ such as a TXA₂ biosynthesis inhibitory activity and/orTXA₂ receptor antagonizing activity, etc.

In accordance with the present invention, there is provided a tricycliccompound [hereafter referred to as Compound (I); compounds having otherformula numbers are similarly referred to] represented by formula (I):##STR6## wherein: represents

(a) single bond or

(b) double bond;

X¹ --X² represents a group selected from:

(a) --CH₂ --O--,

(b) --CH₂ --S--,

(c) --CH₂ --CH₂ -- and

(d) --CH═CH--;

each of G^(A) and G^(B) independently represents a group selected from:

(a) lower alkyl,

(b) halogen and

(c) --OR¹

wherein R¹ represents a group selected from:

(a)' hydrogen and

(b)' lower alkyl

each of g^(A) and g^(B) independently represents 0, 1, 2 or 3;

one of R^(A) and R^(B) represents

(a) hydrogen and

the other represents

(b) --Y--COOR^(1a)

wherein

R^(1a) has the same significance for R¹ as described above,

Y represents:

(a)' single bond

(b)' --CR^(1b) R^(1c) --(CH₂)_(m) -- and

(c)' --CR^(1b) ═CR^(1c) --(CH₂)_(m) -- wherein each of R^(1b) and R^(1c)independently has the same significance for R¹ as described above and, mrepresents 0, 1, 2, 3 or 4, wherein the left side of the formula in (b)'and (c)' is bound to the mother nucleus;

W¹ represents a group selected from:

(a) --S--,

(b) --SO₂ --,

(c) --O--,

(d) --NR^(1d) wherein R^(1d) has the same significance for R¹ asdescribed above,

(e) --NHCO--,

(f) ═N--,

(g) ═CH-- and

(h) --CH₂ --;

wherein the left side of the formula in (e) through (g) is bound to themother nucleus;

n represents 0, 1, 2, 3 or 4;

W² represents a group selected from:

(a) single bond,

(b) --S-- and

(c) --NR^(1e) -- wherein R^(1e) has the same significance for R¹ asdescribed above;

Z represents an aromatic cyclic group selected from: ##STR7## whereineach of a, a¹, a², a³ and a⁴ independently represents a group selectedfrom:

(a)' --CH₂ --

(b)' --NH--,

(c)' --O--,

(d)' --S-- and

(e)' --SO₂ --;

each of b, c, d, d¹, d², d³ and d⁴ independently represents a groupselected from:

(a)' ═CH-- and

(b)' ═N--;

each of Q¹, Q² and Q³ independently represent a group selected from:

(a)' hydrogen,

(b)' lower alkyl,

(c)' benzyl,

(d)' substituted benzyl wherein each substituent on the phenyl in thesubstituted benzyl independently represents 1 to 3 groups selected from:

(a)" halogen and

(b)" --OR^(1f) wherein R^(1f) has the same significance for R¹ asdescribed above;

and, a substituent on the methylene represents one group selected from:

(c)" --OR^(1g) wherein R^(1g) has the same significance for R¹ asdescribed above;

(e)' phenyl,

(f)' halogen,

(g)' --CF₃,

(h)' nitro,

(i)' --CN,

(j)' --N₃,

(k)' --COOR²,

(l)' --OR²,

(m)' --OCOR²,

(n)' --SR²

(o)' --COR²

(p)' --CONR^(2a) R^(2b), wherein each of R^(2a) and R^(2b) independentlyrepresents R², wherein R² represents a group selected from:

(a)" hydrogen,

(b)" straight or branched alkyl having 1 to 18 carbon atoms,

(c)" benzyl and

(d)" phenyl;

(q)' methylenedioxy formed together with the ortho-position;

on the saturated carbon atom (methylene) of (e) and (h) in thedefinition for Z;

(r)'=O and,

(s)'=S

and pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

Examples of the ring constituting the aromatic cyclic group in thedefinition for Z in formula (I) include: (a) pyrrole, pyrazole,imidazole, triazole, thiadiazole, etc.; (b) indole, azaindole,isoindole, indazole, benzimidazole, azabenzimidazole, benzothiazole,benzotriazole, purine, etc.; (c) imidazobenzoquinone, etc.; (d)naphthoimidazole, etc.; (e) indoline, isoindoline, dihydroindazole,dihydrobenzimidazole, etc.; (f) benzene, pyridine, pyrimidine, etc.; (g)naphthalene, quinoline, isoquinoline, etc.; (h) tetrahydroquinoline,tetrahydroisoquinoline, benzothiazine, etc.

In the definition for R² in formula (I), the straight or branched alkylhaving 1 to 18 carbon atoms includes methyl, ethyl, propyl, isopropyl,butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl, octyl,nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl,hexadecyl, heptadecyl, octadecyl, and the like.

In the definition for the respective groups in formula (I), the loweralkyl includes straight or branched alkyl having 1 to 6 carbon atoms,for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, and the like; the halogen includeseach atom of fluorine, chlorine, bromine and iodine.

The pharmaceutically acceptable salt of Compound (I) includes an acidaddition salt, a metal salt, an ammonium salt, an organic amine additionsalt, an amino acid addition salt, etc. which are pharmaceuticallyacceptable.

As the pharmaceutically acceptable acid addition salt of Compound (I),mention may be made of the inorganic acid salt such as hydrochloride,sulfate, phosphate, etc. and the organic acid salt such as acetate,maleate, fumarate, tartarate, citrate, etc. As the pharmaceuticallyacceptable metal salt, the alkali metal salt such as sodium salt,potassium salt, etc.; alkaline earth metal salt such as magnesium salt,calcium salt, etc. and further the aluminum salt and the zinc salt areappropriate. As the ammonium salt, mention may be made of the salt ofammonium, tetramethylammonium, etc. As the pharmaceutically acceptableorganic amine addition salt, mention may be made of an addition salt ofmorpholine, piperidine, etc. As the pharmaceutically acceptable aminoacid addition salt, an addition salt of lysine, glycine, phenylalanineor the like are mentioned.

Hereafter processes for producing Compound (I) are described below butthe production of Compound (I) is not deemed to be limited thereto. Invarious processes, reaction conditions may be appropriately chosen fromthe following conditions.

A reaction solvent may be chosen from water or an organic solvent whichdoes not participate in the reaction and can be used singly or asadmixture. Example of the organic solvent include an alcohol such asmethanol, ethanol, propanol, isopropanol, etc.; and ether such asdiethyl ether, dioxane, tetrahydrofuran, ethylene glycol monomethylether or ethylene glycol dimethyl ether, etc.; a hydrocarbon such asbenzene, toluene, xylene, hexane, cyclohexane, petroleum ether, ligroinor decaline, etc.; a ketone such as acetone, methyl ethyl ketone, etc.an amide such as formamide, dimethylformamide, hexamethylphosphorictriamide, etc.; acetonitrile, ethyl acetate, dimethylsulfoxide,sulfolane or a halogenated hydrocarbon such as methylene chloride,dichloroethane, tetrachloroethane, chloroform or carbon tetrachloride,etc. Further in the case that bases or acids later described are liquid,they may also be used as a solvent.

As the appropriate base, an inorganic or organic base can be used. Thesebases include an alkali metal hydroxide, for example, lithium hydroxide,sodium hydroxide or potassium hydroxide; an alkali metal carbonate, forexample, sodium carbonate, sodium hydrogencarbonate or potassiumcarbonate; an alkali metal acetate, for example, sodium acetate orpotassium acetate; an alkali metal alkoxide, for example, sodiummethoxide, sodium ethoxide or potassium tert-butoxide; or an organicmetal compound, for example, sodium hydride, potassium hydride, lithiumaluminum hydride, lithium borohydride, sodium triethylborohydride,methyl magnesium bromide, ethyl magnesium bromide, vinyl magnesiumbromide, n-butyl lithium, sec-butyl lithium; or an organic amine, forexample, triethylamine, tri-n-butylamine, pyridine,N,N-dimethylaminopyridine, picoline, lutidine, N,N-dimethylaniline,dicyclohexylmethylamine, N-methylpiperidine, morpholine,N-methylmorpholine, diazabicyclooctane, diazabicycloundecene orN-benzyltrimethylammonium hydroxide (Triton B), etc.

As the appropriate acid, an inorganic or organic acid or Lewis acid canbe used. Examples of the inorganic acid include hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid,hypochloric acid, sulfurous acid or nitrous acid, etc. Examples of theorganic acid are formic acid, acetic acid, trifluoroacetic acid, benzoicacid, p-toluenesulfonic acid, camphorsulfonic acid or methanesulfonicacid, etc. Examples of the Lewis acid include aluminum chloride, zincchloride, tin chloride, boron trifluoride, boron trifluoride diethylether complex, titanium tetrachloride, etc.

A reaction temperature is generally from -80° C. to a boiling point of asolvent. It is also possible to heat in the absence of any solvent used.In general, the reaction may be carried out under normal pressure but itis also possible to carry out the reaction under pressure. In this case,the reaction temperature may also be raised to a temperature higher thanthe boiling point of a solvent.

A reaction time is generally in a range of 1 minute to a week.

In the following description, preferred reaction conditions are given.

Further in the following description, for purposes of simplifying thereaction equations, the tricyclic moiety that does not directlyparticipate in the reaction: ##STR8## wherein , X¹ --X², G^(A), G^(B),R^(A), R^(B), g^(A) and g^(B) have the same significances as describedabove; is sometimes referred to as: ##STR9##

Compound (I) can be prepared from Compound (III) or from Compounds(IVa-e) obtained from Compound (III) according to the following reactionsteps: ##STR10## wherein ##STR11## has the same significance asdescribed above; R⁴ represents lower alkyl, Hal represents halogen andPh represents phenyl.

Herein the halogen shown by Hal represents chlorine, bromine and iodineand the lower alkyl is the same as defined for the lower alkyl for eachgroup in formula (I).

Compounds (III) are either described in J. Med. Chem., 19, 941 (1976);ibid., 21, 1035 (1978); ibid., 20, 1557 (1977); ibid., 20, 1499 (1977);ibid., 29, 2347 (1986); ibid., 21, 633 (1978); ibid., 20, 456 (1977);U.S. Pat. Nos. 4,172,949 and 4,282,365, Japanese Published UnexaminedPatent Application Nos. 21679/1983, 28972/1985, 152669/1986,152672/1986, 152673/1986, 152675/1986 and 10784/1988, or can besynthesized according to the methods described in these publications orin a manner similar thereto.

Further the processes for producing Compounds (IVa-e) from Compound(III) can be carried out according to the methods described in JapanesePublished Unexamined Patent Application Nos. 150083/1981, 28972/1985,152670/1986, 152671/1986, 152672/1986, 152675/1986 and 10784/1988, etc.or in a manner similar thereto.

Method 1-1 Synthesis of Compound (Ia) in Compound (I), wherein W¹ isW^(1a) (part 1) ##STR12## wherein W^(1a) is --S--, --SO₂ --, --O-- or--NR^(1d) ; X¹ --X², G^(A), G^(B), R^(A), R^(B), W², Z, R^(1d), g^(A),g^(B) and n have the same significances as described above.

Compound (Ia) can be produced from Compounds (IVa-c) and (Va) accordingto the following reaction steps. ##STR13## wherein A^(a) represents OH,OR⁴ or Hal; ##STR14## W^(1a), W², Z, R⁴, Hal and n have the samesignificances as described above.

Compound (Ia) or acid addition salts thereof (which include, forexample, a hydrochloride, a hydrobromide, an acetate, a trifluoroacetateand p-toluenesulfonate, etc.; in the following description, the acidaddition salts also refer to these salts) can be obtained by reactionCompound (IVa) with 1 to 5 molar equivalents of an appropriatedehydrating and condensing agent, for example, trifluoroaceticanhydride, in an inert solvent such as methylene chloride, chloroform,etc., at a temperature of from 0° C. to room temperature for 1 to 24hours, then adding 1 to 5 molar equivalents of Compound (Va) or acidaddition salts thereof to the reaction solution and reacting the mixturebetween at 0° C. and a boiling point of the solvent, for 1 to 24 hours,if necessary and desired, in the presence of an appropriate acidcatalyst, for example, boron trifluoride diethyl ether complex.

Compound (Ia) or acid addition salts thereof can also be obtained byreacting Compound (IVb) with 1 to 5 molar equivalents of Compound (Va)or acid addition salts thereof in an inert solvent such as methylenechloride, chloroform, etc., between at 0° C. and a boiling point of thesolvent, if necessary and desired, in the presence of an appropriateacid catalyst, for example, boron trifluoride diethyl ether complex, for1 to 24 hours.

Compound (Ia) or acid addition salts thereof can also be obtained byreacting Compound (IVc) with 1 to 10 molar equivalents of Compound (Va)or acid addition salts thereof either in an inert solvent such astoluene, methylene chloride, chloroform, N,N-dimethylformamide, etc., orusing an organic base itself such as pyridine, etc. as a solvent,between at 0° C. and a boiling point of the solvent, if necessary anddesired, in the presence of a base such as triethylamine, pyridine,sodium hydride, etc. for 1 to 48 hours.

Method 1-2 Synthesis of Compound (Ia) (part 2)

Compound (Ia) can also be obtained from Compounds (IVa-c) according tothe following process.

Firstly, Compound (VIIb) or (VIIc) can be obtained from Compounds(IVa-c) according to the following reaction steps. ##STR15## wherein##STR16## A^(a), W^(1a), W², Z, Hal and n have the same significances asdescribed above; and R⁵ represents a group capable of being split asOR⁵.

Herein, R⁵ means an alkylsulfonyl group such as methanesulfonyl,trifluoromethanesulfonyl, etc. or an arylsulfonyl group such asphenylsulfonyl, p-toluenesulfonyl, etc.

The corresponding Compound (VIIa) or (VIIc) can be obtained by reactingCompound (IVa) with 1 to 5 molar equivalents of an appropriatedehydrating and condensing agent, for example, trifluoroaceticanhydride, in an inert solvent such as methylene chloride, chloroform,etc., at a temperature of from 0° C. to room temperature for 1 to 24hours, then adding 1 to 10 molar equivalents of an alcohol (VIa) or itshalide (VIb) to the reaction solution and reacting the mixture betweenat room temperature and a boiling point of the solvent, if necessary anddesired, in the presence of an appropriate acid catalyst, for example,boron trifluoride diethyl ether complex, for 1 to 24 hours.

Compound (VIIa) or (VIIc) can be likewise obtained by reacting Compound(IVb) or (IVc) with 1 to 10 molar equivalents of an alcohol (VIa) or itshalide (VIb) in an inert solvent such as methylene chloride, chloroform,etc., between at room temperature and a boiling point of the solvent, ifnecessary and desired, either in the presence of an appropriate acidcatalyst, for example, boron trifluoride diethyl ether complex, or inthe presence of an appropriate base, for example, triethylamine, for 1to 24 hours.

The thus obtained Compound (VIIa) may be reacted with 1 to 5 molarequivalents of Hal-R⁵ or (R⁵)₂ O (wherein R⁵ and Hal have the samesignificances as described above) at a temperature of from -50° C. toroom temperature for 1 to 24 hours in an inert solvent, for example,methylene chloride, chloroform, etc., if necessary and desired, in thepresence of a base such as pyridine, etc. to give Compound (VIIb).

Furthermore, Compound (VIIc) may also be obtained by reacting Compound(VIIa) with 1 to 5 molar equivalents of a halogenating agent, forexample, thionyl chloride, phosphorus pentachloride, phosphorustribromide, etc., without a solvent or in an inert solvent such asmethylene chloride, chloroform, etc., if necessary and desired, in thepresence of a base such as pyridine, etc., at a temperature of from 0°C. to room temperature for 1 to 24 hours; or by reacting Compound (VIIa)with 1 to 10 molar equivalents of an alkyl halide such as methyl iodideat a temperature of from -20° C. to the boiling point of the solvent, inan inert solvent such as benzene, if necessary and desired, in thepresence of 1 to 10 molar equivalents of triphenylphosphine and 1 to 10molar equivalents of diethyl azodicarboxylate, for 1 to 24 hours; or byreacting Compound (VIIa) with 1 to 10 molar equivalents of ahalogenating agent such as methanesulfonyl chloride, etc., in thepresence of 1 to 10 molar equivalents of a salt such as lithiumchloride, in dimethylformamide at -20° to 100° C. for 1 to 24 hours.

Where Compound (VIIc) is the chloride (Hal═Cl) or bromide (Hal═Br), thecompound may be reacted further with an iodide, for example, sodiumiodide, in a polar solvent such as acetonitrile to give the iodide(Hal═I). Compound (VIIb) can be converted into Compound (VIIc) undersimilar conditions.

Then, Compound (Ia) can be obtained by reacting Compound (VIIb) orCompound (VIIc) with 1 to 10 molar equivalents of Compound (VIII) or itsacid addition salts in an inert solvent such as methylene chloride,chloroform, dichloroethane, N,N-dimethylformamide, dioxane,tetrahydrofuran, etc. or using as a solvent an organic base itself suchas pyridine, etc., if necessary and desired, in the presence of a basesuch as sodium carbonate, triethylamine, pyridine, Triton B, sodiumhydride, potassium hydride, lithium aluminum hydride, lithiumborohydride, sodium triethylborohydride, methyl magnesium bromide, ethylmagnesium bromide, vinyl magnesium bromide, etc., at a temperature offrom -78° C. to a boiling point of the solvent for 1 to 45 hours.

The reaction between Compound (VIIc) and Compound (VIII) can also becarried out in the co-presence of iodide such as sodium iodide,potassium iodide, etc.

Method 2-1 Synthesis of Compound (Ib) in Compound (I), wherein W¹ is--NHCO-- (part 1) ##STR17## wherein X¹ --X², G^(A), G^(B), R^(A), R^(B),W², Z, g^(A), g^(B) and n have the same significance as described above.

Compound (Ib) can be produced according to the following reaction steps.##STR18## wherein ##STR19## W², Z and n have the same significances asdescribed above,

Compound (Ib) can be obtained by reacting Compound (IVd) or acidaddition salts thereof with 1 to 5 molar equivalents of a carboxylicacid (Vb) or reactive derivatives thereof, either in an inert solventsuch as methylene chloride, chloroform, etc., if necessary and desired,in the presence of a base such as pyridine, etc., or using an organicbase itself such as pyridine as the solvent, between at 0° C. and aboiling point of the solvent for 1 to 48 hours.

Herein, the carboxylic acid reactive derivatives include an acid halide(acid chloride, acid bromide, etc.), an acid anhydride (acid anhydrideformed with a dehydrating and condensing agent such asN,N'-dicyclohexylcarbodiimide, etc., in the reaction system,commercially available acid anhydrides, etc.), an activated ester(p-nitrophenyl ester, N-oxysuccinimide ester), a mixed acid anhydride(monoethyl carbonate, monoisobutyl carbonate, etc.) and the like.

Method 2-2 Synthesis of Compound (Ib) (part 2)

Compound (Ib) can also be obtained from Compound (IVd) according to thefollowing reaction steps. ##STR20## wherein ##STR21## W², Z, Hal and nhave the same significances as described above.

Compound (VIId) can be obtained by reacting Compound (IVd) with 1 to 5molar equivalents of an acid halide (VIb) in an inert solvent such asmethylene chloride, chloroform, etc., if necessary and desired, in thepresence of a base such as pyridine, etc., at a temperature of from 0°C. to room temperature for 1 to 24 hours.

The thus obtained Compound (VIId) can be led to Compound (Ib) in amanner similar to the conversion from Compound (VIIc) into Compound (Ia)in Method 1-2.

Method 3 Synthesis of Compound (Ic) in Compound (I), wherein W¹ is ═N--##STR22## wherein X¹ --X², G^(A), G^(B), R^(A), R^(B), W², Z, g^(A),g^(B) and n have the same significances as described above.

Compound (Ic) can be produced according to the following reaction steps.##STR23## wherein ##STR24## W², Z and n have the same significances asdescribed above.

Compound (Ic) can be obtained by reacting Compound (III) with 1 to 10molar equivalents of an amine (Vc) in an inert gas, for example, in theatmosphere of nitrogen, argon, etc., if necessary and desired, in thepresence of a bulky organic base such as 2,6-lutidine,dicyclohexylmethylamine, etc. and 1 to 10 molar equivalents of Lewisacid such as titanium tetrachloride, in an inert solvent, for example,benzene, between at 0° C. and a boiling point of the solvent for 1 to 96hours.

Method 4-1 Synthesis of Compound (Id) in Compound (I), wherein W¹ is═CH-- (part 1) ##STR25## wherein X¹ --X², G^(A), G^(B), R^(A), R^(B),W², Z, g^(A), g^(B) and n have the same significances as describedabove.

Compound (Id) can be produced according to the following reaction steps:##STR26## wherein ##STR27## W², Z, Ph and n have the same significancesas described above.

A phosphonium salt (Vf):

    Ph.sub.3 P.sup.⊕ CH.sub.2 --(CH.sub.2).sub.n --W.sup.2 --Z.Hal.sup.⊖                                     (Vf)

wherein W², Z, Hal, Ph and n have the same significances as describedabove, obtained by reacting triphenylphosphine (Ph₃ P) with a halide[Hal--CH₂ --(CH₂)_(n) --W² --Z (Ve)] is firstly subjected to reaction inan inert solvent, for example, tetrahydrofuran, etc., in the presence ofa molar equivalent of a base such as n-butyl lithium, etc., at atemperature of from 0° C. to room temperature to give an ylide (Vd).

Compound (Id) can be obtained by reaction 1 to 5 molar equivalents,based on Compound (III), of Compound (Vd), after or without isolation,with Compound (III) in an inert solvent, for example, tetrahydrofuran,etc., at a temperature of from 0° C. to a boiling point of the solvent.

Method 4-2 Synthesis of Compound (Id) (part 2)

Compound (Id) can also be produced from Compound (III) according to thefollowing reaction steps. ##STR28## wherein ##STR29## W², Z, Hal and nhave the same significances as described above.

An alcohol (IX) can be obtained by reacting 1 to 5 molar equivalents ofGrignard reagent (Vg) with Compound (III) in an inert solvent such astetrahydrofuran, diethyl ether, etc., at a temperature of from 0° C. toroom temperature for 1 to 48 hours.

Compound (Vg) is formed by reacting the corresponding Compound (Ve) with0.5 to 2 molar equivalents of magnesium in an inert solvent such astetrahydrofuran, diethyl ether, etc., if necessary, in the presence of atrace amount of iodine, at a temperature of from 0° C. to a boilingpoint of the solvent for 0.5 to 12 hours. The Grignard reagent formed isgenerally used for the next reaction as it is, without isolating thesame.

The thus obtained Compound (IX) is subjected to dehydration to giveCompound (Id). For the dehydration, there are used a method whichcomprises the reaction in an inert solvent such as dioxane, etc., in thepresence of an acid, for example, p-toluenesulfonic acid, between atroom temperature and a boiling point of the solvent for 1 to 12 hours; amethod which comprises reaction with a halogenating agent such asthionyl chloride, etc. in an organic base such as pyridine at atemperature of from 0° C. to room temperature for 1 to 12 hours, and thelike.

Method 4-3 Synthesis of Compound (Id) (part 3)

Firstly, the carbonyl group of Compound (III) is converted into Compound(VIIf) according to the following reaction steps. ##STR30## wherein##STR31## Ph and n have the same significances as described above; andR⁶ represents a protective group of hydroxy.

Herein, as the protective group of hydroxy, groups generally used asprotective groups for alcoholic hydroxy can be used and, specifically,tetrahydropyranyl or the like is preferably used.

An ylide (VIc) in which the hydroxy is firstly protected with a suitableprotective group (for example, tetrahydropyranyl, etc.) is formed in aninert solvent, e.g., tetrahydrofuran ]cf., J. Org. Chem., 44, 3760(1979)].

Then, the formed ylide (VIc) is reacted with 0.2 to 1 molar equivalentof Compound (III) at a temperature of from -78° C. to a boiling point ofthe solvent for 1 to 48 hours to give Compound (VIIe).

Compound (VIIe) can be converted into Compound (VIIf) by removing theprotective group. The removal of protective group can be conducted in aconventional manner; in the case of using, for example,tetrahydropyranyl as a protective group, Compound (VIIe) is treated withan acid catalyst such as p-toluenesulfonic acid, hydrochloric acid, etc.in a suitable hydrated solvent such as hydrated dioxane, hydratedtetrahydrofuran, etc., at a temperature of from 0° C. to a boiling pointof the solvent from 1 to 24 hours to give Compound (VIIf).

Compound (VIIf) can be led to Compound (Id) via Compound (VIIg) or(VIIh) according to the following reaction steps. ##STR32## wherein##STR33## W², Z, R⁵, Hal and n have the same significances as describedabove.

The reaction can be performed in a manner similar to the method forleading Compound (VIIa) to Compound (Ia) described in Method 1-2.

Method 4-4 Synthesis of Compound (Id-1) in Compound (Id), wherein n is 1##STR34## wherein X¹ --X², G^(A), G^(B), R^(A), R^(B), W², Z, g^(A) andg^(B) have the same significances as described above.

Compound (Id-1) can be prepared according to the following reactionsteps. ##STR35## wherein ##STR36## W², Z, R⁵ and Hal have the samesignificances as described above; R^(4a) has the same significance forR⁴ as described above; [CH₂ O] represents formaldehyde and/or a polymerthereof; and R^(7a) and R^(7b), which may be the same or different, eachrepresents lower alkyl or may be combined to nitrogen adjacent theretoto form a heterocyclic ring.

Herein, the lower alkyl in the definitions of R^(7a) and R^(7b) has thesame significances for the lower alkyl in formula (I). As theheterocyclic ring formed by R^(7a) and R^(7b), mention may be made ofpyrrolidine, piperidine, N-methylpiperazine, morpholine, thiomorpholine,N-methylhomopiperazine and the like.

Compound (IVe) is reacted with 1 to 10 molar equivalents of formaldehydeand/or a formaldehyde polymer, for example, paraformaldehyde, in ahydrohalogenic acid, preferably hydrochloric acid or in an inertsolvent, for example, dioxane, saturated with hydrogen chloride and, ifnecessary and desired, in the presence of a strong acid such as sulfuricacid or trifluoroacetic acid, at a temperature of from room temperatureto a boiling point of the solvent, for 1 to 24 hours to give Compound(VIIh-1).

Compound (VIIf-1) can be obtained under almost the same conditions asdescribed above except that no hydrohalogenic acid is added.

Furthermore, Compound (VIIh-1) can also be obtained as follows. That is,Compound (IVe) is reacted with 1 to 2 molar equivalents of formaldehydeand/or a polymer thereof, for example, paraformaldehyde, 1 to 3 molarequivalents of a secondary amine (X) and trifluoroacetic acid, in aninert solvent such as methylene chloride, chloroform, dichloroethane,tetrachloroethane, etc., if necessary and desired, in the presence ofacetic acid, between at room temperature and a boiling point of thesolvent, for 1 to 48 hours to give Compound (VIIi-1) or an acid additionsalt thereof. Compound (VIIi-1) can be led to Compound (VIIh-1) byreacting Compound (VIIi-1) with 1 to 10 molar equivalents of ahalocarbonate, preferably ethyl chloroformate if necessary and desired,in the presence of a base such as triethylamine, sodium acetate, etc. inan inert solvent such as methylene chloride, chloroform, dichloroethane,tetrachloroethane, etc., between at 0° C. and a boiling point of thesolvent for 1 to 48 hours.

Furthermore, Compound (VIIh-1) can also be obtained according to thefollowing reaction steps. ##STR37## wherein ##STR38## has the samesignificance as described above, and each of R^(4a) and R^(4b)independently has the same significances for R⁴ as described above.

Compound (III) is reacted with 1 to 10 molar equivalents ofHorner-Emmons reagent (VIf) in an inert solvent such as tetrahydrofuran,etc. at a temperature of from -78° C. to a boiling point of the solventfor 1 to 24 hours, if necessary and desired, in the presence of 1 to 10molar equivalents of a base, preferably sodium hydride, potassiumtert-butoxide, etc. to give Compound (VIIn-1).

Then, the alkoxycarbonyl of the obtained Compound (VIIn-1) isselectively reduced by a suitable reduction method to give Compound(VIIf-1). Preferred reduction is performed either by treating Compound(VIIn-1) with 1 to 10 molar equivalents of lithium aluminum hydride asthe reducing agent in an inert solvent such as diethyl ether, etc. at atemperature of from -78° C. to room temperature for 10 minutes to 24hours, or by treating Compound (VIIn-1) with 1 to 10 molar equivalentsof diisobutyl hydrated aluminum as the reducing agent in an inertsolvent such as tetrahydrofuran, etc. at a temperature of from -100° C.to room temperature for 10 minutes to 24 hours.

The thus obtained Compounds (VIIf-1) and (VIIh-1) can be converted intoCompound (Id-1) according to the method for synthesizing Compound (Id)from corresponding Compounds (VIIf) and (VIIh) described in Method 4-3.

Method 5-1 Synthesis of Compound (Ie) in Compound (I), wherein W¹ is--CH₂ -- (part 1) ##STR39## wherein X¹ --X², G^(A), G^(B), R^(A), R^(B),W², Z, g^(A), g^(B) and n have the same significances as describedabove.

Compound (Ie) can be obtained according to the following reaction step.##STR40## wherein ##STR41## W², Z and n have the same significances asdescribed above.

Compound (Ie) can be obtained by hydrogenating Compound (Id) wherein W¹is ═CH--, in the presence of an appropriate catalyst, for example,palladium-carbon, platinum oxide, Raney nickel, nickel boride or cobaltboride, etc., if necessary and desired, in the co-presence of an acidsuch as hydrochloric acid, in an inert solvent, for example, ethanol,acetic acid, etc. between at 0° C. and a boiling point of the solventfor 1 to 48 hours, under normal pressure to under pressure.

Method 5-2 Synthesis of Compound (Ie) (part 2)

Compound (Ie) can also be prepared from Compound (IVc) according to thefollowing reaction steps. ##STR42## wherein ##STR43## W², Z and n havethe same significances as described above; and each of Hal^(a) andHal^(b) independently has the same significances for Hal as describedabove.

The reaction is carried out under almost the same conditions as in theGrignard reaction for leading Compound (III) to Compound (IX) describedin Method 4-2.

Method 5-3 Synthesis of Compound (Ie) (part 3)

Firstly, Compound (IVc) is converted into Compound (VIIk) according tothe following reaction steps. ##STR44## wherein ##STR45## Hal^(a),Hal^(b), R⁶ and n have the same significances as described above.

Compound (VIIj) is obtained by reacting Grignard reagent (VId) whereinthe hydroxy is protected with an appropriate protective group (forexample, tetrahydropyranyl, etc.) with 0.1 to 1 molar equivalent ofCompound (IVc) at a temperature of -78° C. to a boiling point of thesolvent for 1 to 24 hours in an inert solvent such as tetrahydrofuran,diethyl ether, etc.

Compound (VId) is produced from the corresponding Compound (VIe):

    Hal--CH.sub.2 --(CH.sub.2).sub.n --OR.sup.6                (VIe)

wherein R⁶, Hal and n have the same significances as described above, ina manner similar to the preparation of Grignard reagent (Vg) describedin Method 4-2.

Compound (VIIk) can be obtained by removing the protective group inCompound (VIIj) in a conventional manner, for example, Method 4-3.

Compound (VIIk) can be led to Compound (Ie) via Compound (VII l) or (VIIm) according to the following reaction steps. ##STR46## wherein##STR47## W², Z, R⁵, Hal and n have the same significances as describedabove.

The reaction can be performed in a manner similar to the method forleading Compound (VIIa) to Compound (Ia) described in Method 1-2.

Method 5-4 Synthesis of Compound (Ie-1) in Compound (Ie) wherein n is 1##STR48## wherein X¹ --X², G^(A), G^(B), R^(A), R^(B), W², Z, g^(A) andg^(B) have the same significances as described above.

Compound (Ie-1) can be obtained according to the following reactionsteps. ##STR49## wherein ##STR50## and R^(4b) have the samesignificances as described above.

Compound (VIIn-1) obtained by Method 4-4 is reduced to give Compound(VIIk-1). For the reduction, the reaction is preferably carried outeither in an inert solvent such as tetrahydrofuran, diethyl ether, etc.at a temperature of from 0° C. to a boiling point of the solvent for 1to 24 hours, using, for example, 1 to 10 molar equivalents, based onCompound (VIIn-1), of a reducing agent such as lithium aluminum hydride,or by hydrogenating Compound (VIIn-1) in the presence of a catalyst, forexample, nickel boride or cobalt boride, etc.

The thus obtained Compound (VIIk-1) can be led to Compound (Ie-1) in amanner similar to Method 5-3 for synthesizing Compound (Ie) fromCompound (VIIk). 6,11 EXAMPLE

Method 6 Synthesis of Compound (I-1) in Compound (I), wherein W² issingle bond and Z is substituted or unsubstituted benzimidazolyl(compound having the formula (b) wherein a is --N<, b is ═CH--, C is═N--, each of d¹, d², d³ and d⁴ is ═CH-) ##STR51## wherein X¹ --X²,G^(A), G^(B), R^(A), R^(B), W¹, Q¹, Q², Q³, g^(A), g^(B) and n have thesame significances as described above.

Compound (I-1a) [Compound (I-1) wherein Q¹ is hydrogen] can be obtainedaccording to the following reaction steps. ##STR52## wherein A^(b)represents OR⁵ or Hal; L represents a protective group for amino; and,##STR53## W¹, Q², Q³, R⁵, Hal and n have the same significances asdescribed above.

Herein, the protective group denoted by L includes an acyl group such asacetyl, trifluoroacetyl, etc., a sulfonyl group such as methanesulfonyl,p-toluenesulfonyl, and the like.

Firstly, Compound (VII-1) [Compounds (VIIb), (VIIc), (VIId), (VIIg),(VIIh), (VIIl), (VIIm), etc. ] is reacted with 1 to 10 molar equivalentsof Compound (XI) in an inert solvent, for example, tetrahydrofuran,N,N-dimethylformamide or the like, in the presence of a base such assodium hydride, triethylamine etc. between at -78° C. and a boilingpoint of the solvent for 1 to 48 hours to give Compound (XII).

The thus obtained Compound (XII) is led to Compound (I-1a) via ano-phenylenediamine derivative (XIII). Compound (XIII) can be providedfor the following reaction without isolation. The reduction of nitro andhydrolysis (removal of the protective group) may be preferredsimultaneously or non-preferentially and sequentially; alternatively,Compound (I-1a) can also be obtained by performing reduction of nitroand cyclization simultaneously after hydrolysis.

The reduction of nitro into amino in Compound (XII) can be performed byhydrogenation in an inert solvent such as ethanol, etc. at a temperatureof from room temperature to 200° C. under normal pressure to underpressure, in the presence of a catalyst such as palladium-carbon, etc.Alternatively, the reduction may be performed by treatment with a metalsuch as zinc, tin, iron, etc. or salts thereof and a largely excessiveacid such as hydrochloric acid, sulfuric acid, etc. at a temperature offrom room temperature to a boiling point of the acid used for 1 to 24hours. The reduction using zinc, etc. may also be practiced under basicconditions using an aqueous sodium hydroxide solution instead of theacid.

Furthermore, Compound (I-1a) which is simultaneously cyclized may alsobe prepared by previously removing the protective group throughhydrolysis and then performing the reduction in the co-presence of amolar equivalent of to a largely excessive amount of formic acid.

The protective group L in Compound (XII) can be removed either byreaction in the presence of an acid such as hydrochloric acid, sulfuricacid, p-toluenesulfonic acid, etc. in water or a hydrated solvent suchas hydrated dioxane, etc., at a temperature of from room temperature toa boiling point of the solvent for 1 to 24 hours, or by reaction in thepresence of a base such as sodium hydroxide, potassium hydroxide, etc.in an inert solvent such as methanol, hydrated dioxane, etc., at atemperature of from room temperature to a boiling point of the solventfor 1 to 24 hours.

Furthermore, the cyclization from the o-phenylenediamine derivative(XIII) to Compound (I-1a) can be effected by reaction in the presence ofan equimolar amount of to a largely excessive amount formic acid in aninert solvent such as water, dioxane, etc. or in the absence of anysolvent, preferably in a solvent mixture of formic acid and an aqueoushydrochloric acid solution, if necessary and desired, in the presence ofan acid such as hydrochloric acid, sulfuric acid, etc., at a temperatureof from room temperature to a boiling point of the solvent for 1 to 24hours.

The above cyclization is described by referring to Compound (I-1a) inCompound (I-1) wherein Q¹ is hydrogen; compounds having substituentsother than Q¹ being hydrogen can also be synthesized in a manner similarto the method of converting the o-phenylenediamine derivative intobenzimidazole derivatives [cf., for example, Prest: HeterocyclicCompounds, 40, Inter Science (1981)]. For example, where methyl isdesired for Q¹, acetic acid is used in place of formic acid and theprocedure can be performed in a similar manner.

In case that an asymmetrically substituted benzimidazole (XIV) is usedwhen applying Method 1-2, 2-2, 4-3, 4-4, 5-3 or the like for theproduction of Compound (I-1), a mixture of 2 positional isomers (I-1-1)and (I-1-2) is generally given, as shown in the following reactionsteps. ##STR54## wherein Q represents the substituents other thanhydrogen defined for Q² or Q³ ; and ##STR55## , W¹, A^(b) and n have thesame significances as described above.

These isomers may be isolated in a conventional manner used in organicsynthesis chemistry, for example, recrystallization, columnchromatography, etc. but may be sometimes isolated with difficulty.Accordingly, where the isolation is difficult or either isomer may bewished to obtained selectively, these methods are not alwaysappropriate. Method 6 provides effective means in such a case.

Method 7 Synthesis of Compound (I-2a) in Compound (I), wherein Z isZ^(a) ##STR56## wherein Z^(a) represents a group wherein substituent(s)Q¹, Q² and/or Q³ are/is --OR^(2a), --SR^(2a), --NHR^(2a) or --N(R^(2a))₂; R^(2a) represents alkyl or benzyl in the definitions for R² ; and, ,X¹ --X², G^(A), G^(B), R^(A), R^(B), W¹, W², n, g^(A) and g^(B) have thesame significances as described above.

Compound (I-2a) can be obtained according to the following reactionsteps. ##STR57## wherein Z^(b) represents a group wherein substituent(s)Q¹, Q² and/or Q³ are/is --OH, --SH, --NH₂ ; and, ##STR58## W¹, W²,Z^(a), R^(2a), Hal and n have the same significances as described above.

Compound (I-2a) can be obtained by reacting Compound (I-2b) [compoundsof Compound (I) wherein Z is Z^(b) ] with 1 to 10 molar equivalents ofCompound (XV) in an inert solvent, for example, N,N-dimethylformamide orthe like, if necessary and desired, in the presence of a base such aspyridine, or using as the solvent an organic base itself such aspyridine, etc. at a temperature of from 0° C. to a boiling point of thesolvent for 1 to 48 hours.

Method 8-1 Synthesis of Compound (I-3) in Compound (I), wherein eitherR^(A) or R^(B) is --Y--COOH ##STR59## wherein one of R^(A1) and R^(B1)represents --Y--COOH and the other represents a hydrogen atom; and , X¹--X², G^(A), G^(B), W¹, W², Z, Y, g^(A), g^(B) and n have the samesignificances as described above.

Compound (I-3) can be obtained according to the following reactionsteps. ##STR60## wherein one of R^(A2) and R^(B2) represents --Y--COOR³and the other represents a hydrogen atom; , X¹ --X², G^(A), G^(B), W¹,W², Z, Y, R^(A1), R^(B1), g^(A), g^(B) and n have the same significancesas described above and R³ represents lower alkyl.

Herein, the lower alkyl denoted by R³ has the same significance forR^(1a) as described above.

Compound (I-3) can be obtained by subjecting Compound (I-4)[alkylcarboxylate in Compound (I) wherein either R^(A) or R^(B) is --Y--COOR³] synthesized according to Methods 1 to 7 to an appropriate hydrolysismethod, for example, by reaction with an equimolar amount of to alargely excessive sodium hydroxide or potassium hydroxide, etc. in asolvent mixture of a lower alcohol such as methanol, ethanol, etc. andwater, between at room temperature and a boiling point of the solvent,for 1 to 48 hours.

Method 8-2 Synthesis of Compound (I-3a) in Compound (I-3), wherein Y issingle bond ##STR61## wherein one of R^(A3) and R^(B3) represents --COOHand the other represents a hydrogen atom; and , X¹ --X², G^(A), G^(B),W¹, W², Z, g^(A), g^(B) and n have the same significances are describedabove.

Compound (I-3a) can be obtained according to the following reactionsteps. ##STR62## wherein one of Hal^(A) and Hal^(B) represents Hal andthe other represents a hydrogen atom; and , X¹ --X², G^(A), G^(B), W¹,W², Z, R^(A3), R^(B3), Hal, g^(A), g^(B) and n have the samesignificances as described above.

Compound (I-3a) can be obtained by carboxylating Compound (XVI)synthesized from Compound (III-1) [Compound having at least one halogenas the substituent on the benzene ring in Compound (III) ] in a mannersimilar to Methods 1 to 7.

Carboxylation can be performed by reaction, for example, Compound (XVI)with a molar equivalent of a metallizing agent, e.g., n-butyl lithium,in an inert solvent such as tetrahydrofuran, etc., at a temperature offrom -78° C. to room temperature, for 10 minutes to 12 hours followed byreacting the resulting reaction mixture with an equimolar amount of to alargely excessive amount of carbon dioxide at a temperature of from -78°C. to room temperature, for 10 minutes to 12 hours. Alternatively,Compound (I-3a) can also be obtained by preparing the correspondingGrignard reagent from Compound (XVI) and magnesium in an inert solventsuch as diethyl ether, etc. in a manner similar to Method 4-2 andreacting the reagent with carbon dioxide, and the like method.

Method 9

In the methods for production shown by Methods 1 through 8, where groupsdefined in Compound (I) change under conditions of the Methods or areinappropriate for practicing the method, the groups may be subjected toconventional means used in organic synthesis chemistry, for example,means for protecting functional groups, removing protection, etc. [forexample, cf., Green, Protective Groups in Organic Synthesis, John Wiley& Sons Incorporated (1981)], methods for oxidation, reduction,hydrolysis, etc. [for example, cf., SHIN-JIKKEN KAGAKU KOZA, vols. 14 &15, Maruzen (1977)].

For example, in case that --COOH is desired as the functional group,4,4-dimethyloxazoline, etc. are preferably used as a protective groupfor --COOH (for example, Japanese Published Unexamined PatentApplication No. 10784/1988) in the method in which the correspondingester is hydrolyzed (cf., Method 8-1 described above), in the reactionusing a Grignard reagent (cf., for example, Methods 4-2, 5-2, 5-3 andthe like), in the reaction using reduction (for example, Methods 4-4,5-1, 5-4 and the like) and in the reaction using an organic metalreagent (for example, Method 1-2, etc.). Furthermore, a desired compoundcan be obtained by hydrolyzing, i.e. removing a protective group in acompound similarly obtained by Methods 1 through 7, etc. in which eitherR^(A) or R^(B) is --Y'--CH₂ OR⁸ [wherein Y' represents a group obtainedby removing CH₂ from Y and R⁸ represents a protecting group for hydroxy(e.g., acetyl group, tetrahydropyranyl, etc.)] to convert --Y'--CH₂ OR⁸into --Y'--CH₂ OH and oxidizing the compound.

The intermediates and objective compounds in the respective methodsdescribed above can be isolated and purified by purification methodsconventionally used in organic synthesis chemistry, for example,filtration extraction, washing, drying, concentration,recrystallization, various column chromatographies, etc. Further theintermediates may also be provided in the subsequent reaction, withoutbeing particularly purified.

In Compound (I) obtained by the foregoing methods, compounds wherein W¹is ═CH-- or ═N-- include geometrical isomers of E-form and Z-form withrespect to stereochemistry. In general, the methods described aboveoften give a mixture of these isomers. Isolation and purification ofthese isomers can be made in a conventional manner used in organicsynthesis chemistry, for example, by column chromatography,recrystallization, etc.

It is also possible to isolate the isomers at stages of intermediates(VIIe to VIIi), by the various methods described above.

Further, if desired, E- and Z-forms may be isomerized from each other.This can be made by treating each isomer in a reflux of, e.g., aceticacid, for 1 to 24 hours, in the presence of an appropriate acid catalystsuch as p-toluenesulfonic acid, etc.

In the present invention, Compound (I) includes not only the E/Z isomersdescribed above but also all possible stereoisomers and a mixturethereof.

In case that salts of Compound (I) are desired to obtained, whenCompound (I) is obtained in the form of a salt, Compound (I) may bepurified as it is. Further in case that Compound (I) is obtained in afree form, salts may be formed in a conventional manner.

Furthermore, Compound (I) and pharmaceutical acceptable salts thereofmay also be present in the form of addition products to water or varioussolvents; these adducts are also included in the present invention.

Specific examples of Compound (I) obtained by various methods are shownin Table 1.

Numbering of substitution positions in Table 1 and Table 6 laterdescribed does not necessarily harmonize with the correct nomenclature[cf. (NOTE) below]; but for purpose of simplicity, numbering of thesubstitution positions is systematically made as illustrated below.##STR63##

NOTE

In cycloheptene derivatives (wherein X¹ --X² is --CH₂ --CH₂ -- or--CH═CH--), despite the positional number in the general formula above,for example, a substituent on the carbon at the 2-position in theformula above is correctly given as a substituent at the 3-position.However, in the tables, following the positional numbering in theformula described above, --COOH on the carbon at the 2-position isindicated to be 2-COOH (correctly 3-COOH).

                                      TABLE 1                                     __________________________________________________________________________    X.sup.1 X.sup.2                                                                       (G.sup.A) g.sup.A /(G.sup.B) g.sup.B                                                     W.sup.1 (CH.sub.2).sub.n W.sup.2 Z                                                                    R.sup.A /R.sup.B                                                                          Compound               __________________________________________________________________________                                                           No.                    CH.sub.2 O                                                                            H                                                                                        ##STR64##               2-COOC.sub.2 H.sub.5  2-COOH                                                              1 a 1 b                "       "         "                        2-CH.sub.2 COOCH.sub.3                                                                    2 a                                                               2-CH.sub.2 COOH                                                                           2 b                    "       "         "                        2-CH(CH.sub.3)COOCH.sub.3                                                                 3 a                                                               2-CH(CH.sub.3)COOH                                                                        3 b                    "       "         "                        2-C(CH.sub.3).sub.2 COOCH.sub.3                                               6           4 a                                                               2-C(CH.sub.3).sub.2 COOCH.sub.3                                               1           4 b                    "       "         "                        2-CH.sub.2 CH.sub.2 COOCH.sub.3                                               1           5 a                                                               2-CH.sub.2 CH.sub.2 COOH                                                                  5 b                    "       "         "                        2-CHCHCOOCH.sub.3                                                                         6 a                                                               2-CHCHCOOH  6 b                    "       "                                                                                        ##STR65##               2-COOC.sub.2 H.sub.5  2-COOH                                                              7 a 7 b                "       "                                                                                        ##STR66##               2-COOCH.sub.3  2-COOH                                                                     8 a 8 b                "       "                                                                                        ##STR67##               2-COOC.sub.2 H.sub.5  2-COO(CH.                                               sub.2).sub.3 CH.sub.3                                                                     9 a 9 b 9 c            "       "         "                        2-CH.sub.2 COOCH.sub.3                                                                    10 a                                                              2-CH.sub.2 COOH                                                                           10 b                   CH.sub.2 O                                                                            H                                                                                        ##STR68##               2-COOC.sub.2 H.sub.5  2-COOH                                                              11 a 11 b              "       "                                                                                        ##STR69##               2-COOC.sub.2 H.sub.5  2-COOH                                                              12 a 12 b              "       "                                                                                        ##STR70##               2-COOC.sub.2 H.sub.5  2-COOH                                                              13 a 13 b              "       "                                                                                        ##STR71##               2-COOCH.sub.3  2-COOH                                                                     14 a 14 b              "       "         "                        3-COOCH.sub.3                                                                             15 a                                                              3-COOH      15 b                   "       "         "                        4-COOCH.sub.3                                                                             16 a                                                              4-COOH      16 b                   "       "         "                        9-COOCH.sub.3                                                                             17 a                                                              9-COOH      17 b                   "       9-Br      "                        2-COOCH.sub.3                                                                             18 a                                                              2-COOH      18 b                   "       H                                                                                        ##STR72##               2-COOCH.sub.3  2-COOH                                                                     19 a 19 b              "       "         "                        2-CH.sub.2 COOCH.sub.3                                                                    20 a                                                              2-CH.sub.2 COOH                                                                           20 b                   "       "                                                                                        ##STR73##               2-COOCH.sub.3  2-COOH                                                                     21 a 21 b              CH.sub.2 O                                                                            H                                                                                        ##STR74##               2-COOCH.sub.3  2-COOH                                                                     22 a 22 b              "       "                                                                                        ##STR75##               2-COOCH.sub.3  2-COOH                                                                     23 a 23 b              "       "         "                        2-CH.sub.2 COOCH.sub.3                                                                    24 a                                                              2-CH.sub.2 COOH                                                                           24 b                   "       "                                                                                        ##STR76##               2-COOCH.sub.3  2-COOH                                                                     25 a 25 b              "       "                                                                                        ##STR77##               2-COOCH.sub.3  2-COOH                                                                     26 a 26 b              "       "                                                                                        ##STR78##               2-COOCH.sub.3  2-COOH                                                                     27 a 27 b              "       "                                                                                        ##STR79##               2-COOCH.sub.3  2-COOH                                                                     28 a 28 b              "       "                                                                                        ##STR80##               2-COOCH.sub.3  2-COOH                                                                     29 a 29 b              "       "                                                                                        ##STR81##               2-COOCH.sub.3  2-COOH                                                                     30 a 30 b              "       "                                                                                        ##STR82##               2-COOCH.sub.3  2-COOH                                                                     31 a 31 b              CH.sub.2 O                                                                            H                                                                                        ##STR83##               2-COOCH.sub.3  2-COOH                                                                     32 a 32 b              "       "                                                                                        ##STR84##               2-COOCH.sub.3  2-COOH                                                                     33 a 33 b              "       "                                                                                        ##STR85##               2-COOCH.sub.3  2-COOH                                                                     34 a 34 b              "       "         "                        2-CH.sub.2 COOCH.sub.3                                                                    35 a                                                              2-CH.sub.2 COOH                                                                           35 b                   "       "                                                                                        ##STR86##               2-COOCH.sub.3  2-COOH                                                                     36 a 36 b              "       "                                                                                        ##STR87##               2-COOCH.sub.3  2-COOH                                                                     37 a 37 b              "       "                                                                                        ##STR88##               2-COOCH.sub.3  2-COOH                                                                     38 a  38 b             "       "                                                                                        ##STR89##               2-COOCH.sub.3  2-COOH                                                                     39 a 39 b              "       "                                                                                        ##STR90##               2-COOCH.sub.3  2-COOH                                                                     40 a 40 b              CH.sub.2 O                                                                            H                                                                                        ##STR91##               2-COOCH.sub.3  2-COOH                                                                     41 a 41 b              "       "         "                        9-COOCH.sub.3                                                                             42 a                                                              9-COOH      42 b                   "       9-Br      "                        2-COOCH.sub.3                                                                             43 a                                                              2-COOH      43 b                   "       9-OCH.sub.3                                                                             "                        2-COOCH.sub.3                                                                             44 a                                                              2-COOH      44 b                   "       H                                                                                        ##STR92##               2-COOCH.sub.3  2-COOH                                                                     45 a 45 b              "       "                                                                                        ##STR93##               2-COOCH.sub.3  2-COOH                                                                     46 a 46 b              "       "                                                                                        ##STR94##               2-COOCH.sub.3  2-COOH                                                                     47 a 47 b              "       "                                                                                        ##STR95##               2-COOCH.sub.3  2-COOH                                                                     48 a 48 b              CH.sub.2 O                                                                            H                                                                                        ##STR96##               2-COOCH.sub.3  2-COOH                                                                     49 a 49 b              "       "                                                                                        ##STR97##               2-COOCH.sub.3  2-COOH                                                                     50 a 50 b              "       "                                                                                        ##STR98##               2-COOCH.sub.3  2-COOH                                                                     51 a 51 b              "       "                                                                                        ##STR99##               2-COOCH.sub.3  2-COOH                                                                     52 a 52 b              "       "                                                                                        ##STR100##              2-COOCH.sub.3  2-COOH                                                                     53 a 53 b              "       "                                                                                        ##STR101##              2-COOCH.sub.3  2-COOH                                                                     54 a 54 b              "       "                                                                                        ##STR102##              2-COOCH.sub.3  2-COOH                                                                     55 a 55 b              CH.sub.2 O                                                                            H                                                                                        ##STR103##              2-COOCH.sub.3  2-COOH                                                                     56 a 56 b              "       "                                                                                        ##STR104##              2-COOCH.sub.3  2-COOH                                                                     57 a 57 b              "       "                                                                                        ##STR105##              2-COOCH.sub.3  2-COOH                                                                     58 a 58 b              "       "                                                                                        ##STR106##               2-COOCH.sub.3  2-COOH                                                                    59 a 59 b              "       "                                                                                        ##STR107##              2-COOCH.sub.3  2-COOH                                                                     60 a 60 b              "       "                                                                                        ##STR108##              2-COOCH.sub.3  2-COOH                                                                     61 a 61 b              CH.sub.2 O                                                                            H                                                                                        ##STR109##              2-COOCH.sub.3  2-COOH                                                                     62 a 62 b              "       "                                                                                        ##STR110##              2-COOCH.sub.3  2-COOH                                                                     63 a 63 b              "       "                                                                                        ##STR111##              2-COOCH.sub.3  2-COOH                                                                     64 a 64 b              "       "                                                                                        ##STR112##              2-COOCH.sub.3  2-COOH                                                                     65 a 65 b              "       "                                                                                        ##STR113##              2-COOCH.sub.3  2-COOH                                                                     66 a 66 b              "       "                                                                                        ##STR114##              2-COOCH.sub.3  2-COOH                                                                     67 a 67 b              CH.sub.2 O                                                                            H                                                                                        ##STR115##              2-COOCH.sub.3  2-COOH                                                                     68 a 68 b              "       "                                                                                        ##STR116##              2-COOCH.sub.3  2-COOH                                                                     69 a 69 b              "       "                                                                                        ##STR117##              2-COOCH.sub.3  2-COOH                                                                     70 a 70 b              "       "                                                                                        ##STR118##              2-COOCH.sub.3  2-COOH                                                                     71 a 71 b              "       "                                                                                        ##STR119##              2-COOCH.sub.3  2-COOH                                                                     72 a 72 b              "       "                                                                                        ##STR120##              2-COOCH.sub.3  2-COOH                                                                     73 a 73 b              CH.sub.2 O                                                                            H                                                                                        ##STR121##              2-COOCH.sub.3  2-COOH                                                                     74 a 74 b              "       "                                                                                        ##STR122##              2-COOCH.sub.3  2-COOH                                                                     75 a 75 b              "       "                                                                                        ##STR123##              2-COOCH.sub.3  2-COOH                                                                     76 a 76 b              "       "                                                                                        ##STR124##              2-COOCH.sub.3  2-COOH                                                                     77 a 77 b              "       "                                                                                        ##STR125##              2-COOCH.sub.3  2-COOH                                                                     78 a 78 b              CH.sub.2 O                                                                            H                                                                                        ##STR126##              2-COOCH.sub.3  2-COOH                                                                     79 a 79 b              "       "                                                                                        ##STR127##              2-COOCH.sub.3  2-COOH                                                                     80 a 80 b              "       "                                                                                        ##STR128##              2-COOCH.sub.3  2-COOH                                                                     81 a 81 b              "       "                                                                                        ##STR129##              2-COOCH.sub.3  2-COOH                                                                     82 a 82 b              "       "                                                                                        ##STR130##              2-COOCH.sub.3  (R = CH.sub.3)                                                 2-COOH (R = H)                                                                            83 a 83 b              CH.sub.2 O                                                                            H                                                                                        ##STR131##              2-COOCH.sub.3  (R = CH.sub.3)                                                 2-COOH (R = H)                                                                            84 a 84 b              "       "                                                                                        ##STR132##              2-COOCH.sub.3  2-COOH                                                                     85 a 85 b              "       "                                                                                        ##STR133##              2-COOCH.sub.3  2-COOH                                                                     86 a 86 b              "       "                                                                                        ##STR134##              2-COOCH.sub.3  2-COOH                                                                     87 a 87 b              "       "                                                                                        ##STR135##              2-COOCH.sub.3  2-COOH                                                                     88 a 88 b              "       "                                                                                        ##STR136##              2-COOCH.sub.3  2-COOH                                                                     89 a 89 b              CH.sub.2 O                                                                            H                                                                                        ##STR137##              2-CH.sub.2 COOCH.sub.3                                                        2-CH.sub.2 COOH                                                                           90 a 90 b              "       "         "                        2-CH(CH.sub.3)COOCH.sub.3                                                                 91 a                                                              2-CH(CH.sub.3)COOH                                                                        91 b                   "       "         "                        2-C(CH.sub.3).sub.2 COOCH.sub.3                                                           92 a                                                              2-C(CH.sub.3).sub.2 COOH                                                                  92 b                   "       "         "                        3-COOCH.sub.3                                                                             93 a                                                              3-COOH      93 b                   "       "         "                        9-COOCH.sub.3                                                                             94 a                                                              9-COOH      94 b                   "       "                                                                                        ##STR138##              2-COOCH.sub.3  2-COOH                                                                     95 a 95 b              "       "                                                                                        ##STR139##              2-COOCH.sub.3  2-COOH                                                                     96 a 96 b              CH.sub.2 O                                                                            H                                                                                        ##STR140##              2-COOCH.sub.3  2-COOH                                                                     97 a 97 b              "       "                                                                                        ##STR141##              2-COOCH.sub.3  2-COOH                                                                     98 a 98 b              "       "                                                                                        ##STR142##              2-COOCH.sub.3  2-COOH                                                                     99 a 99 b              "       "                                                                                        ##STR143##              2-COOCH.sub.3  2-COOH                                                                     100 a 100 b            "       "                                                                                        ##STR144##              2-COOCH.sub.3  2-COOH                                                                     101 a 101 b            "       "                                                                                        ##STR145##              2-COOCH.sub.3  2-COOH                                                                     102 a 102 b            CH.sub.2 O                                                                            H                                                                                        ##STR146##              2-COOCH.sub.3  2-COOH                                                                     103 a 103 b            "       "                                                                                        ##STR147##              2-COOCH.sub.3  2-COOH                                                                     104 a 104 b            "       "                                                                                        ##STR148##              2-COOCH.sub.3  2-COOH                                                                     105 a 105 b            "       "                                                                                        ##STR149##              2-COOCH.sub.3  2-COOH                                                                     106 a 106 b            "       "                                                                                        ##STR150##              2-COOCH.sub.3  2-COOH                                                                     107 a 107 b            "       "                                                                                        ##STR151##              2-COOCH.sub.3  2-COOH                                                                     108 a 108 b            CH.sub.2 O                                                                            H                                                                                        ##STR152##              2-COOCH.sub.3  2-COOH                                                                     109 a 109 b            "       "                                                                                        ##STR153##              2-COOCH.sub.3  2-COOH                                                                     110 a 110 b            "       "                                                                                        ##STR154##              2-COOCH.sub.3  2-COOH                                                                     111 a 111 b            "       "                                                                                        ##STR155##              2-COOCH.sub.3  2-COOH                                                                     112 a 112 b            "       "                                                                                        ##STR156##              2-COOCH.sub.3  2-COOH                                                                     113 a 113 b            "       "                                                                                        ##STR157##              2-COOCH.sub.3  2-COOH                                                                     114 a 114 b            CH.sub.2 O                                                                            H                                                                                        ##STR158##              2-COOCH.sub.3  2-COOH                                                                     115 a 115 b            "       "                                                                                        ##STR159##              2-COOCH.sub.3  2-COOH                                                                     116 a 116 b            "       "                                                                                        ##STR160##              2-COOCH.sub.3  2-COOH                                                                      117 a 117 b           "       "                                                                                        ##STR161##              2-COOCH.sub.3  2-COOH                                                                     118 a 118 b            "       "                                                                                        ##STR162##              2-COOCH.sub.3  2-COOH                                                                     119 a 119 b            "       "                                                                                        ##STR163##              2-COOCH.sub.3  2-COOH                                                                     120 a 120 b            "       "                                                                                        ##STR164##              2-COOCH.sub.3  2-COOH                                                                     121 a 121 b            CH.sub.2 O                                                                            H                                                                                        ##STR165##              2-COOCH.sub.3  2-COOH                                                                     122 a 122 b            "       "                                                                                        ##STR166##              2-COOCH.sub.3  2-COOH                                                                     123 a 123 b            "       "                                                                                        ##STR167##              2-COOCH.sub.3  2-COOH                                                                     124 a 124 b            "       "                                                                                        ##STR168##              2-COOCH.sub.3  2-COOH                                                                     125 a 125 b            "       "                                                                                        ##STR169##              2-CH.sub.2 COOCH.sub.3                                                        2-CH.sub.2 COOH                                                                           126 a 126 b            "       "                                                                                        ##STR170##              2-CH.sub.2 COOCH.sub.3                                                        2-CH.sub.2 COOH                                                                           127 a 127 b            "       "                                                                                        ##STR171##              2-COOCH.sub.3  2-COOH                                                                     128 a 128 b            CH.sub.2 O                                                                            H                                                                                        ##STR172##              2-COOCH.sub.3  2-COOH                                                                     129 a 129 b            "       "                                                                                        ##STR173##              2-COOCH.sub.3  2-COOH                                                                     130 a 130 b            "       "                                                                                        ##STR174##              2-COOCH.sub.3  2-COOH                                                                     131 a 131 b            "       "                                                                                        ##STR175##              2-COOCH.sub.3  2-COOH                                                                     132 a 132 b            "       "                                                                                        ##STR176##              2-COOCH.sub.3  2-COOH                                                                     133 a 133 b            "       "                                                                                        ##STR177##              2-COOCH.sub.3  2-COOH                                                                     134 a 134 b            "       "                                                                                        ##STR178##              2-COOCH.sub.3  2-COOH                                                                     135 a 135 b            CH.sub.2 O                                                                            H                                                                                        ##STR179##              2-COOCH.sub.3  2-COOH                                                                     136 a 136 b            "       "                                                                                        ##STR180##              2-COOCH.sub.3  2-COOH                                                                     137 a 137 b            "       "                                                                                        ##STR181##              2-COOCH.sub.3  2-COOH                                                                     138 a 138 b            "       "                                                                                        ##STR182##              2-COOCH.sub.3  2-COOH                                                                     139 a 139 b            "       "                                                                                        ##STR183##              2-COOCH.sub.3  2-COOH                                                                     140 a 140 b            "       "                                                                                        ##STR184##              2-COOCH.sub.3  2-COOH                                                                     141 a 141 b            "       "                                                                                        ##STR185##              2-COOCH.sub.3  2-COOH                                                                     142 a 142 b            "       "                                                                                        ##STR186##              2-COOCH.sub.3  2-COOH                                                                     143 a 143 b            CH.sub.2 O                                                                            H                                                                                        ##STR187##              2-COOCH.sub.3  2-COOH                                                                     144 a 144 b            "       "                                                                                        ##STR188##              2-COOCH.sub.3  2-COOH                                                                     145 a 145 b            "       "                                                                                        ##STR189##              2-COOCH.sub.3  2-COOH                                                                     146 a 146 b            "       "                                                                                        ##STR190##              2-COOCH.sub.3  2-COOH                                                                     147 a 147 b            "       "                                                                                        ##STR191##              2-COOCH.sub.3  2-COOH                                                                     148 a 148 b            "       "                                                                                        ##STR192##              2-COOCH.sub.3  2-COOH                                                                     149 a 149 b            "       "                                                                                        ##STR193##              2-COOCH.sub.3  2-COOH                                                                     150 a 150 b            "       "                                                                                        ##STR194##              2-COOCH.sub.3  2-COOH                                                                     151 a 151 b            CH.sub.2 O                                                                            H                                                                                        ##STR195##              2-COOCH.sub.3  2-COOH                                                                     152 a 152 b            "       "                                                                                        ##STR196##              2-COOCH.sub.3  2-COOH                                                                     153 a 153 b            "       "                                                                                        ##STR197##              2-COOCH.sub.3  2-COOH                                                                     154 a 154 b            "       "                                                                                        ##STR198##              2-COOCH.sub.3  2-COOH                                                                     155 a 155 b            "       "                                                                                        ##STR199##              2-COOCH.sub.3  2-COOH                                                                     156 a 156 b            "       "                                                                                        ##STR200##              2-COOCH.sub.3  2-COOH                                                                     157 a 157 b            "       "                                                                                        ##STR201##              2-COOCH.sub.3  2-COOH                                                                     158 a 158 b            "       "                                                                                        ##STR202##              2-COOCH.sub.3  2-COOH                                                                     159 a 159 b            CH.sub.2 O                                                                            H                                                                                        ##STR203##              2-COOCH.sub.3  2-COOH                                                                     160 a 160 b            "       "                                                                                        ##STR204##              2-COOCH.sub.3  2-COOH                                                                     161 a 161 b                               ##STR205##              2-COOCH.sub.3  2-COOH                                                                     162 a 162 b            "       "                                                                                        ##STR206##              2-COOCH.sub.3  2-COOH                                                                     163 a 163 b            "       "                                                                                        ##STR207##              2-COOCH.sub.3  2-COOH                                                                     164 a 164 b            "       "                                                                                        ##STR208##              2-COOCH.sub.3  2-COOH                                                                     165 a 165 b            CH.sub.2 S                                                                            "                                                                                        ##STR209##              2-COOCH.sub.3  2-COOH                                                                     166 a 166 b            "       "                                                                                        ##STR210##              2-COOCH.sub.3  2-COOH                                                                     167 a 167 b            CH.sub.2 S                                                                            H                                                                                        ##STR211##              2-COOCH.sub.3  2-COOH                                                                     168 a 168 b            "       "                                                                                        ##STR212##              2-COOCH.sub.3  2-COOH                                                                     169 a 169 b            "       "                                                                                        ##STR213##              2-COOCH.sub.3  2-COOH                                                                     170 a 170 b            CH.sub.2 CH.sub.2                                                                     "                                                                                        ##STR214##              2-COOCH.sub.3  2-COOH                                                                     171 a 171 b            "       "                                                                                        ##STR215##              2-COOCH.sub.3  2-COOH                                                                     172 a 172 b            "       "                                                                                        ##STR216##              2-COOCH.sub.3  2-COOH                                                                     173 a 173 b            "       "                                                                                        ##STR217##              2-COOCH.sub.3   2-COOH                                                                    174 a 174 b            CH.sub.2 CH.sub.2                                                                     H                                                                                        ##STR218##              2-COOCH.sub.3  2-COOH                                                                     175 a 175 b            CHCH    "                                                                                        ##STR219##              2-COOCH.sub.3  2-COOH                                                                     176 a 176 b            "       "                                                                                        ##STR220##              2-COOCH.sub.3  2-COOH                                                                     177 a 177 b            "       "                                                                                        ##STR221##              2-COOCH.sub.3  2-COOH                                                                     178 a 178 b            "       "         "                        2-CH.sub.2 COOCH.sub.3                                                                    179 a                                                             2-CH.sub.2 CO                                                                              179 b                 "       "                                                                                        ##STR222##              2-COOCH.sub.3  2-COOH                                                                     180 a 180 b            "       "                                                                                        ##STR223##              2-COOCH.sub.3  2-COOH                                                                     181 a 181              __________________________________________________________________________                                                           b                  

The thus prepared Compound (I) possesses a potent TXA₂ biosynthesisinhibitory activity and/or TXA₂ receptor antagonizing activity, andparticularly preferred compounds are shown in Table 2.

The compound shown in Table 2, example, reference examples are shown bycorrect nomenclature.

                  TABLE 2                                                         ______________________________________                                                                   Compound                                           Compound                   No.                                                ______________________________________                                        11-[(3-Pyridyl)methyl]amino-6,11-dihydrodibenz-                                                          9c                                                 [b,e]oxepin-2-carboxylic acid                                                 11-[(3-Pyridyl)methyl]thio-6,11-dihydrodibenz-                                                           14b                                                [b,e]oxepin-2-carboxylic acid                                                 11-[(3-Pyridyl)methyl]oxy-6,11-dihydrodibenz-                                                            21b                                                [b,e]oxepin-2-carboxylic acid                                                 11-[(3-Pyridyl)methyl]imino-6,11-dihydrodibenz-                                                          25b                                                [b,e]oxepin-2-carboxylic acid                                                 11-(3-Pyridine)carboxamido-6,11-dihydrodibenz-                                                           30b                                                [b,e]oxepin-2-carboxylic acid                                                 11-[2-(3-Pyridyl)ethylidene]-6,11-dihydrodibenz-                                                         36b                                                [b,e]oxepin-2-carboxylic acid                                                 11-[2-(3-Pyridyl)ethyl]-6,11-dihydrodibenz[b,e]-                                                         40b                                                oxepin-2-carboxylic acid                                                      11-[2-(1-Benzimidazolyl)ethylidene]-6,11-dihydro-                                                        41b                                                dibenz[b,e]oxepin-2-carboxylic acid                                           9-Bromo-11-[2-(1-benzimidazolyl)ethylidene]-6,11-                                                        43b                                                dihydrodibenz[b,e]oxepin-2-carboxylic acid                                    11-[2-(5-Methyl-1-benzimidazolyl)ethylidene]-                                                            47b                                                6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid                               11-[2-(6-Methyl-1-benzimidazolyl)ethylidene]-                                                            48b                                                6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid                               11-[2-(5-Chloro-1-benzimidazolyl)ethylidene]-6,11-                                                       53b                                                dihydrodibenz[b,e]oxepin-2-carboxylic acid                                    11-[2-(6-Chloro-1-benzimidazolyl)ethylidene]-6,11-                                                       54b                                                dihydrodibenz[b,e]oxepin-2-carboxylic acid                                    11-[2-(5-Nitro-1-benzimidazolyl)ethylidene]-6,11-                                                        55b                                                dihydrodibenz[b,e]oxepin-2-carboxylic acid                                    11-[2-(6-Nitro-1-benzimidazolyl)ethylidene]-6,11-                                                        56b                                                dihydrodibenz[b,e]oxepin-2-carboxylic acid                                    11-[2-(5-Methoxy-1-benzimidazolyl)ethylidene]-                                                           61b                                                6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid                               11-[2-(6-Methoxy-1-benzimidazolyl)ethylidene]-                                                           62b                                                6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid                               11-[2-(5-Benzyloxy-1-benzimidazolyl)ethylidene]-                                                         67b                                                6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid                               11-[2-(6-Benzyloxy-1-benzimidazolyl)ethylidene]  -                                                       68b                                                6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid                               11-[2-(5-Methylthio-1-benzimidazolyl)ethylidene]-                                                        69b                                                6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid                               11-[2-(6-Methylthio-1-benzimidazolyl)ethylidene]-                                                        70b                                                6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid                               11-[2-(5-Acetyl-1-benzimidazolyl)ethylidene]-6,11-                                                       75b                                                dihydrodibenz[b,e]oxepin-2-carboxylic acid                                    11-[2-(6-Acetyl-1-benzimidazolyl)ethylidene]-6,11-                                                       76b                                                dihydrodibenz[b,e]oxepin-2-carboxylic acid                                    11-[2-(5-Benzoyl-1-benzimidazolyl)ethylidene]-                                                           77b                                                6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid                               11-[2-(6-Benzoyl-1-benzimidazolyl)ethylidene]-                                                           78b                                                6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid                               11-[2-(5-Benzyl-1-benzimidazolyl)ethylidene]-6,11-                                                       79b                                                dihydrodibenz[b,e]oxepin-2-carboxylic acid                                    11-[2-(6-Benzyl-1-benzimidazolyl)ethylidene]-6,11-                                                       80b                                                dihydrodibenz[b,e]oxepin-2-carboxylic acid                                    11-[2-[5-Hydroxy(phenyl)methyl-1-benzimidazolyl]-                                                        81b                                                ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-                                  carboxylic acid                                                               11-[2-[6-Hydroxy(phenyl)methyl-1-benzimidazolyl]-                                                        82b                                                ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-                                  carboxylic acid                                                               11-[2-(5,6-Dimethyl-1-benzimidazolyl]ethylidene]-                                                        89b                                                6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid                               11-[2-(4,5-Dimethyl-1-benzimidazolyl]ethylidene]-                                                        96b                                                6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid                               11-[2-(6,7-Dimethyl-1-benzimidazolyl]ethylidene]-                                                        97b                                                6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid                               11-[2-(4,7-Dimethyl-1-benzimidazolyl]ethylidene]-                                                        98b                                                6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid                               11-[2-(5,6-Methylenedioxy-1-benzimidazolyl)-                                                             100b                                               ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-                                  carboxylic acid                                                               11-[2-(5,6-Dimethoxy-1-benzimidazolyl)ethylidene]-                                                       101b                                               6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid                               11-[2-(4,7-Dimethoxy-1-benzimidazolyl)ethylidene]-                                                       103b                                               6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid                               11-[2-(Imidazo-p-benzoquinon-1-yl)ethylidene]-                                                           105b                                               6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid                               11-[2-(2-Methylthio-1-benzimidazolyl)ethylidene]-                                                        113b                                               6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid                               11-[2-(3-Indolyl)ethylidene]-6,11-dihydrodibenz-                                                         122b                                               [b,e]oxepin-2-carboxylic acid                                                 11-[2-(1-Methyl-3-indolyl)ethylidene]-6,11-                                                              123b                                               dihydrodibenz[b,e]oxepin-2-carboxylic acid                                    11-[2-(5-Methoxy-3-indolyl)ethylidene]-6,11-                                                             124b                                               dihydrodibenz[b,e]oxepin-2-carboxylic acid                                    11-[2-(2-Benzimidazolyl)ethyl]thio-6,11-dihydro-                                                         129b                                               dibenz[b,e]oxepin-2-carboxylic acid                                           11-[2-(1-Methyl-2-benzimidazolyl)ethyl]thio-6,11-                                                        130b                                               dihydrodibenz[b,e]oxepin-2-carboxylic acid                                    11-[2-(1-Benzyl-2-benzimidazolyl)ethyl]thio-6,11-                                                        131b                                               dihydrodibenz[b,e]oxepin-2-carboxylic acid                                    11-[2-(1-Acetyl-2-benzimidazolyl)ethyl]thio-6,11-                                                        133b                                               dihydrodibenz[b,e]oxepin-2-carboxylic acid                                    11-[2-(5-Methoxy-2-benzimidazolyl)ethyl]thio-6,11-                                                       134b                                               dihydrodibenz[b,e]oxepin-2-carboxylic acid                                    11-[2-(1-Benzyl-5-methoxy-2-benzimidazolyl)ethyl]-                                                       135b                                               thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic                               acid                                                                          11-[2-[1-(4-Methoxybenzyl)-5-methoxy-2-benz-                                                             136b                                               imidazolyl]ethyl]thio-6,11-dihydrodibenz[b,e]-                                oxepin-2-carboxylic acid                                                      11-[2-(1-Benzoyl-5-methoxy-2-benzimidazolyl)-                                                            137b                                               ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-                                   carboxylic acid                                                               11-[2-[(2-Quinolyl)thio]ethylidene]-6,11-dihydro-                                                        140b                                               dibenz[b,e]oxepin-2-carboxylic acid                                           11-[2-[(3-Hydroxy-2-pyridyl)thio]ethylidene]-                                                            141b                                               6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid                               11-[2-[(1,2,3,4-Tetrahydroisoquinolin)-2-yl]-                                                            158b                                               ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-                                   carboxylic acid                                                               11-[2-[(6,7-Dimethoxy-1,2,3,4-tetrahydroiso-                                                             161b                                               quinolin)-2-yl]ethyl]thio-6,11-dihydrodibenz-                                 [b,e]  oxepin-2-carboxylic acid                                               11-[3-[(1,2,3,4-Tetrahydroisoquinolin-2-yl]-                                                             162b                                               propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-                                 carboxylic acid                                                               11-[2-[(2-Hydroxy)phenyl]ethyl]oxy-6,11-dihydro-                                                         165b                                               dibenzb,e]oxepin-2-carboxylic acid                                            11-(3-Pyridyl)methylthio-6,11-dihydrodibenzo[b,e]-                                                       166b                                               thiepin-2-carboxylic acid                                                     11-[2-(1-Benzimidazolyl)ethylidene]-6,11-dihydro-                                                        168b                                               dibenzo[b,e]thiepin-2-carboxylic acid                                         11-[2-(5,6-Dimethyl-1-benzimidazolyl)ethylidene]-                                                        169b                                               6,11-dihydrodibenzo[b,e]thiepin-2-carboxylic acid                             11-[2-(5,6-Dimethoxy-1-benzimidazolyl)ethylidene]-                                                       170b                                               6,11-dihydrodibenzo[b,e]thiepin-2-carboxylic acid                             5-(3-Pyridyl)methylthio-10,11-dihydro-5H-dibenzo-                                                        171b                                               [a,d]cyclohepten-3-carboxylic acid                                            5-[2-(1-Benzimidazolyl)ethylidene]-10,11-dihydro-                                                        172b                                               5H-dibenzo[a,d]cyclohepten-3-carboxylic acid                                  5-[2-(5,6-Dimethyl-1-benzimidazolyl)ethylidene]-                                                         173b                                               10,11-dihydro-5H-dibenzo[a,d]cyclohepten-3-                                   carboxylic acid                                                               5-[2-(5,6-Dimethoxy-1-benzimidazolyl)ethylidene]-                                                        175b                                               10,11-dihydro-5H-dibenzo[a,d]cyclohepten-3-                                   carboxylic acid                                                               5-(3-Pyridyl)methylthio-5H-dibenzo[a,d]cyclo-                                                            176b                                               hepten-3-carboxylic acid                                                      5-[2-(1-Benzimidazolyl)ethylidene]-5H-dibenzo-                                                           177b                                               [a,d]cyclohepten-3-carboxylic acid                                            5-[2-(5,6-Dimethyl-1-benzimidazolyl)ethylidene]-                                                         178b                                               5H-dibenzo[a,d]cyclohepten-3-carboxylic acid                                  5-[2-(5,6-Dimethoxy-1-benzimidazolyl)ethylidene]-                                                        181b                                               5H-dibenzo[a,d]cyclohepten-3-carboxylic acid                                  ______________________________________                                    

TEXT EXAMPLES

Next, pharmacological activities of Compound (I) are described below.

Acute Toxicity Test

Using three dd strain male mice weighing 20±1 g, a test compound wasorally (po; 300 mg/kg) or intraperitoneally (ip; 100 mg/kg)administered. MLD (the minimum lethal dose) was determined by observingthe mortality for seven days after administration.

The results are shown in Table 3.

Test on Anti Aggregatory Effects (TXA₂ -Antagonizing Action)

Using guinea pig platelet, influence of the compounds on plateletaggregation induced by U-46619(9,11-dideoxy-9α,11a-methanoepoxyprostaglandin F₂α ; manufactured byCayman Chemical Co., Ltd.) which was TXA₂ /prostaglandin H₂ receptorstimulant was examined.

Male guinea pig (Hartley strain; body weight, 300 to 600 g) wasanesthesized by intraperitoneal administration of sodium pentobarbital(30 mg/kg) and blood was collected from the descending aorta of theabdomen with a 1/10 volume of 3.8% trisodium citrate. By centrifugation(KC-70: manufactured by Kubota Co., Ltd.) at 800 rpm for 15 minutes,platelet rich plasma (PRP) was obtained. Platelet aggregation induced byU-46619 (0.5-1 μM) was determined by photometry [Born, G. V. R. et al.,Nature (London), 194, 927-929 (1962)]. A test compound was pretreatedfor 3 minutes and the ability to inhibit aggregation was determined. Theminimum concentration which inhibits platelet aggregation by 30% or morewas defined as the minimum effective concentration (MEC) of the testcompound.

The results are shown in Table 3.

TXA₂ Biosynthesis Inhibitory Test

After a mixture of 70 μl (40 μg of protein, 100 mM Tris-hydrochloridebuffer, pH 7.4) of bovine platelet microsome and 10 μl (10%methanol-containing 100 mM Tris-hydrochloride buffer) of a test compoundsolution was settled at 0° C. for 5 minutes, 20 μl of prostaglandin H₂solution (0.1 nmol, in Tris-hydrochloride buffer described abovecontaining 20% acetone) as substrate was added to the mixture. Fiveminutes after, 2.9 ml of stopping solution [100 mM, Tris-hydrochloridebuffer containing 0.1 μM of OKY-1581; Tromb. Res. 23, 145 (1981)] wasadded to stop the reaction.

TXA₂ was unstable in the buffer solution, and non-enzymaticallyconverted to TXB₂. An amount of thromboxane B₂ (TXB₂) formed in thereaction solution was determined by radioimmunoassay [F. A. Fitzpatricket al., Methods in Enzymology, 86, 286 (1982)]. An inhibition rate ofthe test compound was calculated according to the following equation.##EQU1##

The amount of TXB₂ formed in control refers to a value obtained when thesame reaction was carried out, using a solvent containing no testcompound.

The amount of TXB₂ formed in blank refers to a value obtained when thereaction was carried out in the system in which the stopping solutionwas added prior to adding substrate.

The results are shown in Table 3.

                  TABLE 3                                                         ______________________________________                                                                         TXA.sub.2 Biosyn-                            Test     Acute Toxicity                                                                            TXA.sub.2   thesis Inhibitory                            Compound (MLD)       Antagonizing                                                                              Activity                                     Compound mg/kg       Activity (MEC)                                                                            Inhibition Rate                              No.*.sup.4                                                                             po      ip      μg/ml  in 10 μM (%)                            ______________________________________                                         9c      >300    >100    30        100                                         14b     >300    >100    3         100                                         25b     >300    >100    1         100                                        E-37b'   >300    >100    3         94                                         E-41b'   >300    >100    0.1       61                                         E-61b    --      --      0.1        1                                         E-62b    --      --      1         11                                         E-89b'   >300    >100    0.1       28                                         E-101b   >300    >100    0.3       17                                         129b'    >300    >100    0.3       66                                         E-156b   >300    >100    1.0       -10                                        158b'    >300    >100    1.0       56                                         165b'    >300    >100    3.0       34                                         BM13505*.sup.1                                                                         >300    >100    0.1        8                                         (reference                                                                    compound)                                                                     OKY 1581*.sup.2                                                                        >300    >100    30        100                                        (reference                                                                    compound)                                                                     KW 4679*.sup.3                                                                         >300    >100    30         1                                         (reference                                                                    compound)                                                                     ______________________________________                                         *.sup.1                                                                       ##STR224##                                                                    *.sup.2                                                                       ##STR225##                                                                    *.sup.3                                                                       ##STR226##                                                                    (Japanese Published Unexamined Patent Application No. 10784/88)               *.sup.4 In Compound No., symbol ' indicates an addition product of the        corresponding compound in Tables 1 and 2 to a salt or solvent and symbols     E and Z represent Eform and Zform, respectively (the same shall apply         hereinafter)                                                             

As demonstrated in Table 3, Compound (I) and pharmaceutically acceptablesalts thereof possess a TXA₂ receptor antagonizing activity or a TXA₂biosynthesis inhibitory activity and some compounds possess bothactivities.

Antithrombotic Activity

Effect of a test compound on thrombus formation on cotton thread whichwas kept in an extracorporeal circulation path for the artery and veinin anesthesized rats was examined in a manner similar to the method ofSmith et al. [Br. J. Pharmacol., 77, 29 (1982)].

Wistar male rats weighing 250 to 400 g were anesthesized byintraperitoneal administration of sodium pentobarbital at a dose of 30mg/kg and an extracorporeal circulation path made of a polyethylene tubehaving a length of 30 cm extending from the right carotid artery to theleft jugular vein was installed. Cotton thread (No. 30) having a lengthof 5.5 cm was inserted into the circulation path and a weight ofthrombus formed on the cotton thread during blood perfusion for 15minutes was measured. Similar operations were performed twice and thetotal weight of thrombus formed by the two blood perfusions was shown asthe weight of thrombus.

A suspension of the test compound in 0.3% carboxymethyl cellulose wasforcedly administered to rats orally in a dose of 1 mg/100 g of rat bodyweight, 2 hours, prior to the initiation of the test, using a gastictube for oral administration to small animals.

The results as shown in Table 4.

                  TABLE 4                                                         ______________________________________                                        Antithrombotic Activity in Rat                                                             Dose      Number of Weight of.sup.a)                             Compound No. (mg/kg)   animals   Thrombus (mg)                                ______________________________________                                        Control group                                                                              --        12        22.4 ± 1.2                                E-41b'       0.3       6         20.2 ± 1.8                                             1         6         16.9 ± 2.5*                                            3         6         14.2 ± 1.4**                                           10        5         13.5 ± 1.5**                              Control group                                                                              --        11        25.9 ± 1.2                                BM13177.sup.b)                                                                             30        5         24.8 ± 1.8                                (reference compound)                                                                       100       5         18.9 ± 1.8**                              ______________________________________                                         .sup.a) mean value ± standard error                                        *P < 0.05,                                                                    **P < 0.01 (indicates a significant difference against the weight of          thrombus in the control group)                                                .sup.b)                                                                       ##STR227##                                                               

This experimental system is considered to be a simple animal model forextracorporeal blood circulation. Therefore, the effectiveness of thecompound in accordance with this invention shown in Table 4 demonstratesthat the compound could be a useful inhibitor (antithrombotic agent)against the formation of thrombus which is a problem in e.g., blooddialysis (in renal insufficiency), etc.

However, the effectiveness of the compounds in accordance with thisinvention is not limited to the disease and condition described above.

Compound (I) or pharmaceutically acceptable salts thereof may beadministered singly as they are but in general, it is preferablyadministered as various medical preparations. These medical preparationsare used for animals and human beings.

The medical preparation in accordance with the present invention maycontain, as an active ingredient, Compound (I) or pharmaceuticallyacceptable salts thereof singly or as admixture with other optionaleffective components for different treatment. Further these medicalpreparations can be produced by optional procedures well known in thepharmaceutical field, by mixing the active ingredient together with oneor more pharmaceutically acceptable carriers.

Herein, as the other effective components for treatment containedtogether with Compound (I) or pharmaceutically acceptable salts thereof,mention may be made of, for example, a steroid, a non-steroid, aperipheral anti-inflammatory agent, a leucotriene antagonist, aleucotriene biosynthesis inhibitor, an H₂ receptor antagonist, ananti-histaminic agent, a histamine release inhibitor, a bronchodilator,an angiotensin converting enzyme inhibitor, a thromboxane A₂biosynthesis inhibitor, an H⁺ -K⁺ ATPase inhibitor, a coronary dilator,a calcium antagonist, a calcium channel operator, a diuretic, a xanthineoxidase inhibitor, a cerebral circulation improving agent, a celebralmetabolism activator, a cerebral protecting agent, a liver protectingagent, an antiplatelet agent, a thrombolytic agent, an adrenaline αreceptor antagonist, an adrenergic β receptor agent, an adrenaline βreceptor antagonist, a serotonine antagonist, a platelet activationfactor (PAF) antagonist, a phospholipase A₂ inhibitor, an adenosinereceptor operator, an adenosine receptor antagonist, anantihyperlipidemic agent, a cholesterol biosynthesis inhibitor, animmunostimulating agent, an immunosuppressive agent, an anticancer agentetc.

It is preferred that the most effective route for treatment be selectedas a route for administration. Oral or parenteral administration such asintrarectal, topical, intranasal, intraocular, intrabuccal,subcutaneous, intramuscular and intravenous routes, etc. are mentioned.

As the form of administration, there are a capsule, a tablet, a granule,a powder, a syrup, an emulsion, a suppository, an ointment, an eyedrop,a nosedrop, a troche, an aerosol, an injection, etc.

A liquid preparation suited for oral administration, for example, anemulsion and a syrup can be prepared using water; sugars such assucrose, sorbitol, fructose, etc.; glycols such as polyethylene glycol,propylene glycol, etc.; oils such as sesame oil, olive oil, soybean oil,etc.; antiseptics such as a p-hydroxybenzoic acid ester, etc.; flavorssuch as strawberry flavor, peppermint, etc. Further a capsule, a tablet,a powder and a granule, etc. can be prepared using an excipient such aslactose, glucose, sucrose, mannitol, etc.; a disintegrator such asstarch, sodium alginate, etc.; a lubricant such as magnesium stearate,talc, etc.; a binder such as polyvinyl alcohol, hydroxypropyl cellulose,gelatin, etc.; a surfactant such as an aliphatic ester, etc.; aplasticizer such as glycerine, etc.

A preparation suited for parenteral administration is composed of asterile aqueous preparation containing active compounds which arepreferably isotonic to blood of recipient. For example, with aninjection, a solution for injection is prepared using carriers composedof a saline solution, a glucose solution or a mixture of saline waterand glucose solution.

A nasal spray preparation is composed of a purified aqueous solution ofthe active compounds which contains an antiseptic and an isotonic agent.Such a preparation is adjusted to pH compatible with nasal membrane andto an isotonic state.

An ocular preparation is prepared in a manner similar to the nasalspray, except that pH and isotonic factors are controlled so as to fitthose of eyes.

A topical preparation is prepared by dissolving or suspending the activecompound in one or more media, for example, a mineral oil, petroleum, apolyvalent alcohol or other bases used for topical medical preparations.

A preparation for rectal administration is provided as a suppositoryusing conventional carriers, for example, cacao fat, hydrogenated fat orhydrogenated fat carboxylic acid, etc.

Further these parenteral preparations may also be added with one or moreauxiliary components such as a diluent, a fragrance, an antiseptic(including an antioxidant), an excipient, a disintegrator, a lubricant,a binder, a surfactant, a plasticizer and the like as indicated in caseof oral administration.

Effective dose and number of administration of Compound (I) orpharmaceutically acceptable salts thereof vary depending upon mode ofadministration, age and body weight of the patient and properties orseverity of conditions to be treated. In general, daily dose is 0.01 to1000 mg/person and number of administration is once a day, or the dosagemay be divided into several ones.

Hereafter, the present invention is described by referring to Examplesand Reference Examples below.

In the description in Tables 5-1 through 5-18 in the following examples,symbols " and "' in the compound numbering represent an addition productof the corresponding compound to a salt or solvent as in the symbol 'described above, and * in recrystallization solvent representssolidification by tritylation.

EXAMPLE 1 Ethyl11-[(3-pyridyl)methyl]amino-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 9a)

Ethyl 11-hydroxy-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compoundc), 6.0 g, obtained in Reference Example 3 was suspended in 100 ml ofmethylene chloride and 3 ml of thionyl chloride was dropwise added tothe suspension under ice cooling. The mixture was stirred at roomtemperature for an hour. The solvent was distilled off under reducedpressure to give oily ethyl11-chloro-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate.

The ester wad dissolved in 20 ml of methylene chloride without isolationand purification. Under ice cooling, the solution was dropwise added to100 ml of methylene chloride solution of 8 ml of 3-aminomethylpyridineand 6 ml of N,N-dicyclohexylmethylamine. After the dropwise addition,the mixture was stirred at room temperature for further 12 hours. Thesolvent was distilled off under reduced pressure. The resulting residuewas subjected to silica gel column chromatography (eluting solvent,hexane:ethyl acetate:triethylamine=10:10:2) to give 3.9 g of the crudeproduct. The obtained crude product was recrystallized from hexane togive 2.3 g of the desired product.

EXAMPLE 2 Butyl11-[(3-pyridyl)methyl]amino-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 9b)

This compound was prepared in a manner similar to Example 1, using butyl11-hydroxy-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound d)obtained in Reference Example 4 and 3-aminomethylpyridine.

EXAMPLE 3 Butyl11-[(3-pyridyl)methyl]amino-6,11-dihydrodibenz[b,e]oxepin-2-carboxylatedihydrochloride monohydrate (Compound 9b')

Compound 9b, 1.7 g, obtained in Example 2 was dissolved in 100 ml ofisopropanol and 2 ml of 7N hydrochloric acid/isopropanol solution wasadded to the solution and the mixture was stirred. After stirring, themixture was ice cooled. The precipitated solid was taken by filtrationand further washed with ether to give 1.0 g of the desired product.

EXAMPLE 4 Ethyl11-(3-pyridyl)amino-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 1a) EXAMPLE 5 Methyl11-(3-pyridyl)amino-6,11-dihydrodibenz[b,e]oxepin-2-acetate (Compound2a) EXAMPLE 6 Ethyl11-(4-pyridyl)amino-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 7a) EXAMPLE 7 Methyl11-[(3-pyridyl)methyl]amino-6,11-dihydrodibenz[b,e]oxepin-2-acetate(Compound 10a) EXAMPLE 8 Ethyl11-[(4-pyridyl)methyl]amino-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 11a) EXAMPLE 9 Methyl2-methyl-2-[11-(3-pyridyl)amino-6,11-dihydrodibenz[b,e]oxepin-2-yl]propionate(Compound 4a)

In Examples 4 through 9, the products were prepared in a manner similarto Example 1, using the corresponding11-hydroxy-6,11-dihydrodibenz[b,e]oxepin derivative (Compound c, f or g)and 3- or 4-aminomethylpyridine.

EXAMPLE 10 Ethyl11-[(4-pyridyl)methyl]amino-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate0.5 fumarate 0.2 hydrate (Compound 11a')

Compound 11a, 2.5 g, obtained in Example 8 was dissolved in 100 ml ofisopropanol and 0.8 g of fumaric acid was added to the solution. Afterstirring at room temperature for an hour, the solvent was distilled offunder reduced pressure. The obtained crude product was recrystallizedfrom acetonitrile-ethanol to give 0.9 g of the desired product.

EXAMPLE 11 Ethyl11-[(2-pyridyl)methyl]amino-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 12a) EXAMPLE 12 Ethyl11-benzylamino-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound13a) EXAMPLE 13 Ethyl11-(2-benzimidazolyl)methyl-amino-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 128a)

In Examples 11 through 13, the products were prepared using thecorresponding 11-hydroxy-6,11-dihydrodibenz[b,e]oxepin derivatives(Compound b or c) and an amino compound in a manner similar to Example1.

Physicochemical properties of the compounds obtained in Examples 1 to 13are shown in Table 5-1.

                                      TABLE 5-1                                   __________________________________________________________________________    Example   MP °C.                                                       No.       (Solvent                                                            (Com-     for                 IR                                              pound                                                                              Appear-                                                                            recrystal-                                                                         NMR            (Method)                                                                            Elemental analysis                        No.) ance lization)                                                                          (Solvent) δ, ppm                                                                       cm.sup.-1                                                                           %                                         __________________________________________________________________________    1    white                                                                              79-81.5                                                                            (CDCl.sub.3) 1.36(t, J=7.3Hz, 3H),                                                           (CHCl.sub.3)                                                                        C.sub.22 H.sub.22 N.sub.2 O.sub.3         (9a) crystal                                                                            (hexane)                                                                           2.15(bs, 1H), 3.70(s, 2H),                                                                   2950, 1705,                                                                             C  H  N                                              4.30(q, J=7.3Hz, 2H), 4.67                                                                   1610, 1285,                                                                         Found                                                                             73.98                                                                            6.01                                                                             7.42                                           (s, 1H), 4.81&6.65(ABq, J=                                                                   1240  Calcd.                                                                            73.78                                                                            5.92                                                                             7.48                                           11.9Hz, 2H), 6.83-7.97(m,                                                     9H), 8.28-8.59(m, 2H)                                          2    pale --   (CDCl.sub.3) 0.80-1.81(m, 7H),                                                               (CHCl.sub.3)                                                                        --                                        (9b) yellow    2.08(bs, 1H), 3.71(s, 2H),                                                                   3040, 2874,                                          oil       4.24(t, J=6.1Hz, 2H), 4.67                                                                   1699, 1612,                                                    (s, 1H), 4.82&6.65(ABq, J=                                                                   1286, 1120                                                     11.9Hz, 2H), 6.58-7.95(m,                                                     9H), 8.24-8.56(m, 2H)                                          3    white                                                                              188-191                                                                            --             --    C.sub.25 H.sub.26 N.sub.2 O.sub.3.2HCl                                        .H.sub.2 O                                (9b')                                                                              solid                                                                              (ether)*                      C  H  N                                                                   Found                                                                             61.02                                                                            6.03                                                                             5.61                                                                Calcd.                                                                            60.85                                                                            6.13                                                                             5.68                            4    color-                                                                             143-145                                                                            (CDCl.sub.3) 1.34(t, J=7.4Hz, 3H),                                                           (CHCl.sub.3)                                                                        C.sub.22 H.sub.20 N.sub.2 O.sub.3         (1a) less      4.29(q, J=7.4Hz, 2H), 4.82                                                                   2960, 1705,                                                                             C  H  N                                    amor-     (bs, 1H), 5.39(s, 1H), 5.05&                                                                 1595, 1240                                                                          Found                                                                             73.43                                                                            5.50                                                                             7.72                                 phous     6.07(ABq, J=13.1Hz, 2H),                                                                           Calcd.                                                                            73.32                                                                            5.59                                                                             7.77                                           6.74-8.18(m, 11H)                                              5    pale --   (CDCl.sub.3) 3.45(s, 2H), 3.53                                                               --    --                                        (2a) yellow    (s, 3H), 4.95&5.80(ABq, J=                                          amor-     14Hz, 2H), 5.30(s, 1H), 6.70-                                       phous     7.50(m, 9H), 7.82(m, 1H),                                                     7.95(bs, 1H)                                                   6    white                                                                              202-203                                                                            (CDCl.sub.3 +DMSO-d.sub.6) 1.30(t,                                                           --    C.sub.22 H.sub.20 N.sub.2 O.sub.3         (7a) solid                                                                              (ethyl                                                                             J=7.1Hz, 3H), 3.35(s, 1H),                                                                             C  H  N                                         acetate)                                                                           4.24(q, J=7.1Hz, 2H), 5.14&                                                                        Found                                                                             73.02                                                                            5.61                                                                             7.70                                           5.89(ABq, J=13.3Hz, 2H), 5.73                                                                      Calcd.                                                                            73.11                                                                            5.86                                                                             7.75                                           (d, J=6.4Hz, 1H), 6.51-8.08                                                   (m, 11H), 9.72(s, 1H)                                          7    pale --   (CDCl.sub.3) 3.48(s, 2H), 3.60                                                               --    --                                        (10a)                                                                              yellow    (s, 3H), 3.67(s, 2H), 4.53                                          oil       (s, 1H), 4.80&6.32(ABq, J=                                                    13Hz, 2H), 6.70-7.68(m, 9H),                                                  8.30-8.60(m, 2H)                                               8    color-                                                                             --   (CDCl.sub.3) 1.36(t, J=7.2Hz, 3H),                                                           --    --                                        (11a)                                                                              less      3.71(bs, 2H), 4.30(q, J=                                            oil       7.2Hz, 2H), 4.65(s, 1H), 4.81                                                 &6.64(ABq, J=12.6Hz, 2H),                                                     6.76-7.91(m, 9H), 8.32-8.61                                                   (m, 2H)                                                        9    color-                                                                             --   (CDCl.sub.3) 1.53(s, 6H), 3.61(s,                                                            (CHCl.sub.3)                                                                        [MS (m/z): 388(M.sup.+)]                  (4a) less      3H), 5.04&5.81(ABq, J=14.2                                                                   1726, 1586,                                          oil       Hz, 2H), 5.36(d, J=6.2Hz, 1H),                                                               1496, 1149,                                                    6.80-7.55(m, 9H), 7.94(bs,                                                                   1126                                                           1H), 8.13(bs, 1H)                                              10   white                                                                              133-134                                                                            --             --    C.sub.25 H.sub.24 N.sub.2 O.sub.5.0.2H                                        .sub.2 O                                  (11a')                                                                             crystal                                                                            (aceto-                       C  H  N                                         nitrile-                  Found                                                                             68.89                                                                            5.62                                                                             6.38                                      ethanol)                  Calcd.                                                                            68.86                                                                            5.64                                                                             6.42                            11   pale 99-100                                                                             (CDCl.sub.3 +D.sub.2 O) 1.36(t, J=7.5                                                        (CHCl.sub.3)                                                                        C.sub.23 H.sub.22 N.sub.2 O.sub.3         (12a)                                                                              yellow                                                                             (hexane)                                                                           Hz, 3H), 2.57(bs, 1H), 3.80                                                                  2984, 1707,                                                                             C  H  N                                    solid     (s, 2H), 4.28(q, J=6.9Hz, 2H),                                                               1613, 1287,                                                                         Found                                                                             73.54                                                                            5.82                                                                             7.39                                           4.65(s, 1H), 4.77&6.68(ABq,                                                                  1121  Calcd.                                                                            73.78                                                                            5.92                                                                             7.48                                           J=11.9Hz, 2H), 6.70-8.67(m,                                                   11H)                                                           12   color-                                                                             82-83                                                                              (CDCl.sub.3) 1.35(t, J=7.2Hz, 3H),                                                           (neat)                                                                              C.sub.24 N.sub.23 HO.sub.3                (13a)                                                                              less (hexane)                                                                           1.94(bs, 1H), 3.67(s, 2H),                                                                   2980, 1710,                                                                             C  H  N                                    crystal   4.28(q, J=7.2Hz, 4H), 4.64(s,                                                                1610, 1500,                                                                         Found                                                                             77.22                                                                            6.21                                                                             3.63                                           1H), 4.79&6.71(ABq, J=11.3                                                                   1245, 1120                                                                          Calcd.                                                                            77.19                                                                            6.21                                                                             3.75                                           Hz, 2H), 6.66-7.99(m, 12H)                                     13   pale --   (CDCl.sub.3) 3.73(s, 3H), 3.83                                                               (CHCl.sub.3)                                                                        --                                        (128a)                                                                             yellow    (bs, 2H), 4.57&6.27(ABq,                                                                     3450, 2950,                                          amor-     J=12.5Hz, 2H), 4.52(s, 1H),                                                                  2394, 1714,                                          phous     6.63-8.10(m, 11H)                                                                            1613, 1289,                                                                   1169                                            __________________________________________________________________________

EXAMPLE 1411-[(3-Pyridyl)methyl]amino-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound 9c)

Compound 9a, 3.9 g, obtained in Example 1 was heated to reflux for anhour in a solvent mixture of 200 ml of methanol, 50 ml of water and 10ml of 10N sodium hydroxide aqueous solution. The solvent was distilledoff under reduced pressure and 4N hydrochloric acid aqueous solution wasadded to the residue to adjust pH to 7. After concentrating underreduced pressure, the residue was subjected to high porous polymer(HP-10; manufactured by Mitsubishi Chemical Industry Co., Ltd.) columnchromatography (eluting solvent; methanol) to give 2.5 g of the crudeproduct. The crude product was recrystallized from water to give 2.0 gof the desired product.

EXAMPLE 1511-(3-Pyridyl)amino-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid(Compound 1b)

Compound 1a, 2.0 g, obtained in Example 4 was hydrolyzed in a mannersimilar to Example 14. After completion of the reaction, the solvent wasdistilled off under reduced pressure and the residue was diluted withwater. To the dilution was added 4N hydrochloric acid aqueous solutionto adjust pH to 7. The precipitated solid was taken out by filtrationand washed with ether to give 1.7 g of the desired product.

EXAMPLE 16 11-(3-Pyridyl)amino-6,11-dihydrodibenz[b,e]oxepin-2-aceticacid (Compound 2b) EXAMPLE 17 0.1 Isopropyl2-methyl-2-[11-(3-pyridyl)amino-6,11-dihydrodibenz[b,e]oxepin-2-yl]propionate(Compound 4b') EXAMPLE 1811-(4-Pyridyl)amino-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid 0.5hydrate (Compound 7b') EXAMPLE 1911-[(3-Pyridyl)methyl]amino-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid(Compound 10b) EXAMPLE 2011-[(2-Pyridyl)methyl]amino]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid 0.5 hydrate (Compound 12b') EXAMPLE 2111-Benzylamino-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid (Compound13b) EXAMPLE 2211-(2-Benzimidazolyl)methylamino-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid monohydrate (Compound 128b')

In Examples 16 through 22, the products were prepared by hydrolyzingesters of the corresponding oxepine derivatives in a manner similar toExample 14 or 15.

Physicochemical properties of the compounds obtained in Examples 14 to22 are shown in Table 5-2.

                                      TABLE 5-2                                   __________________________________________________________________________    Example   MP °C.                                                       No.       (Solvent                                                            (Com-     for                  IR                                             pound                                                                              Appear-                                                                            recrystal-                                                                          NMR            (Method)                                                                            Elemental analysis                       No.) ance lization)                                                                           (Solvent) δ, ppm                                                                       cm.sup.-1                                                                           %                                        __________________________________________________________________________    14   white                                                                              190-191                                                                             (DMSO-d.sub.6) 3.62&3.79(ABq,                                                                (KBr  C.sub.21 H.sub.18 N.sub.2 O.sub.3        (9c) crystal                                                                            (water)                                                                             J=14.0Hz, 2H), 4.80(s, 1H),                                                                  tablet)   C  H  N                                              5.01&6.61(ABq, J=12.0Hz,                                                                     3600-2700,                                                                          Found                                                                             72.75                                                                            5.22                                                                             8.05                                           2H), 6.83(d, J=8.5Hz, 1H),                                                                   1690, 1610,                                                                         Calcd.                                                                            72.82                                                                            5.24                                                                             8.09                                           7.28-7.88(m, 8H), 8.40-8.45                                                                  1235, 1110                                                     (m, 2H)                                                       15   white                                                                              258 (dec.)                                                                          --             --    C.sub.20 H.sub.16 N.sub.2 O.sub.3        (1b) solid                                                                              (water)                        C  H  N                                                                   Found                                                                             72.00                                                                            4.81                                                                             8.04                                                                Calcd.                                                                            72.28                                                                            4.85                                                                             8.43                           16   pale --    (DMSO-d.sub.6) 3.21(s, 2H), 5.14                                                             --     --                                      (2b) yellow     (d, J=13.4Hz, 1H), 5.68(m,                                         amor-      1H), 5.80(d, J=13.4Hz, 1H),                                        phous      6.73(d, J=8.3Hz, 1H), 7.00-                                                   7.16(m, 3H), 7.24-7.33(m,                                                     4H), 7.60(m, 1H), 7.72(m,                                                     1H), 8.16(s, 1H)                                              17   white                                                                              181-182.5                                                                           (DMSO-d.sub.6) 5.15&5.86(ABq,                                                                (KBr  C.sub.23 H.sub.22 N.sub.2 O.sub.3.0.1                                         C.sub.6 H.sub.14 O                       (4b')                                                                              crystal                                                                            (isopro-                                                                            J=13.2Hz, 2H), 5.76(d, J=6.8                                                                 tablet)   C  H  N                                        pylether)                                                                           Hz, 1H), 6.82(d, J=8.5Hz, 1H),                                                               1695, 1580,                                                                         Found                                                                             73.78                                                                            6.05                                                                             7.09                                           6.9-7.45(m, 7H), 7.66(d, J=                                                                  1497, 1318,                                                                         Calcd.                                                                            73.69                                                                            6.13                                                                             7.28                                           7.3Hz, 1H), 7.74(d, J=4.6Hz,                                                                 1225, 1131,                                                    1H), 8.18(d, J=2.7Hz, 1H)                                                                    1008                                           18   white                                                                              258-259                                                                             --             --    C.sub.20 H.sub.16 N.sub.2 O.sub.3.0.5                                         H.sub.2 O                                (7b')                                                                              solid                                                                              (isopro-                       C  H  N                                        panol)                     Found                                                                             70.46                                                                            4.85                                                                             8.11                                                                Calcd.                                                                            70.40                                                                            5.02                                                                             8.21                           19   pale --    (DMSO-d.sub.6) 3.35(s, 2H), 4.61                                                             --    --                                       (10b)                                                                              yellow     (s, 1H), 4.87(d, J=12.4Hz,                                         amor-      1H), 6.36(d, J=12.2Hz, 1H),                                        phous      6.70(d, J=8.1Hz, 1H), 7.03(m,                                                 2H), 7.24-7.34(m, 5H), 7.68                                                   (d, J=7.8Hz, 1H), 8.41(m, 2H)                                 20   pale unclear                                                                             (DMSO-d.sub.6) 3.71&3.80(ABq, J=                                                             (KBr  C.sub.21 H.sub.18 N.sub.2 O.sub.3.0.5                                         H.sub.2 O                                (12b')                                                                             yellow     14.7Hz, 2H), 4.82(s, 1H),                                                                    tablet)   C  H  N                                   solid      4.97&6.58(ABq, J=11.8Hz,                                                                     1683, 1609,                                                                         Found                                                                             70.76                                                                            5.09                                                                             7.97                                           2H), 6.82(d, J=8.4Hz, 1H),                                                                   1384, 1233,                                                                         Calcd.                                                                            70.97                                                                            5.39                                                                             7.88                                           7.21-7.75(m, 8H), 7.88(d, J=                                                                 1114, 1006                                                     2.2Hz, 1H), 8.49(d, J=4.0Hz,                                                  1H)                                                           21   white                                                                              145-147                                                                             (DMSO-d.sub.6) 3.60&3.64(ABq, J=                                                             (KBr  C.sub.22 H.sub.19 NO.sub.3               (13b)                                                                              solid                                                                              (water)                                                                             13.8Hz, 2H), 4.77(s, 1H),                                                                    tablet)   C  H  N                                              5.01&6.64(ABq, J=11.8Hz,                                                                     3180, 1609,                                                                         Found                                                                             76.61                                                                            5.54                                                                             3.90                                           2H), 6.83(d, J=8.5Hz, 1H),                                                                   1562, 1364,                                                                         Calcd.                                                                            76.50                                                                            5.54                                                                             4.06                                           7.20-7.44(m, 9H), 7.71(dd,                                                                   1237, 1016                                                     J=2.2&8.5Hz, 1H), 7.85(d,                                                     J=2.2Hz, 1H)                                                  22   yellow                                                                             --    (DMSO-d.sub.6) 3.83&3.92(ABq,                                                                --    C.sub.23 H.sub.19 N.sub.3 O.sub.3.H.s                                         ub.2 O                                   (128b')                                                                            solid      J=14.9Hz, 2H), 4.95(s, 1H),                                                                            C  H  C                                              5.00&6.59(ABq, J=12.1Hz,                                                                           Found                                                                             68.20                                                                            4.89                                                                             10.59                                          2H), 6.87(d, J=8.5Hz, 1H),                                                                         Calcd.                                                                            68.47                                                                            5.25                                                                             10.42                                          7.13-7.53(m, 8H), 7.74(dd,                                                    J=2.2&8.5Hz, 1H), 7.96(d,                                                     J=2.2Hz, 1H)                                                  __________________________________________________________________________

EXAMPLE 23 Methyl(Z,E)-11-[2-(1-imidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 37a)

In a solvent mixture of 230 ml of toluene and 30 ml ofN,N-dimethylformamide, 5.0 g of methyl(Z,E)-11-(2-chloroethylidene)-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound h; Z/E=1/9) obtained in a manner similar to Reference Example8 and 4.8 g of imidazole were heated to reflux for 6 hours. Afterallowing to cool, the solvent was distilled off under reduced pressure.The obtained residue was extracted with 500 ml of methylene chloride andwashed successively with saturated sodium bicarbonate aqueous solutionand saturated sodium chloride aqueous solution. After drying overanhydrous magnesium sulfate, the solvent was distilled off under reducedpressure. The resulting residue was subjected to silica gel columnchromatography (eluting liquid; methanol:ethylacetate:triethylamine=1:10:1) to give 5.8 g of the product (Z/E=1/9).

EXAMPLE 24 Methyl(E)-11-[2-(1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-41b)

Methyl(E)-11-(2-chloroethylidene)-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound h), 4.0 g, obtained in Reference Example 8 and 6.0 g ofbenzimidazole were treated in a manner similar to Example 23 to give 4.1g of the desired product.

EXAMPLE 25 Methyl(E)-11-[2-(5-nitro-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylateCompound E-55a) and methyl(E)-11-[2-(6-nitro-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-56a)

Compound h, 2.0 g, and 5.2 g of 5-nitrobenzimidazole were treated in amanner similar to Example 23 to give a 1:1 mixture of Compounds E-55aand E-56a. The mixture was separated and purified by silica gel columnchromatography (eluting solvent, hexane:ethylacetate:triethylamine=10:10:1) to give 1.1 g of methyl(E)-11-[2-(5-nitro-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-55a) and 0.7 g of methyl(E)-11-[2-(6-nitro-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-56a).

EXAMPLE 26 Methyl(E)-11-[2-(5-methoxy-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-61a) and methyl(E)-11-[2-(6-methoxy-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-62a)

Compound h, 2.9 g, and 4.2 g of 5-methoxybenzimidazole were treated in amanner similar to Example 23 to give a 1:1 mixture of Compounds E-61aand E-62a. The mixture was separated and purified by silica gel columnchromatography (eluting solvent, hexane:ethylacetate:triethylamine=10:10:1) to give 0.8 g of methyl(E)-11-[2-(5-methoxy-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-61a), 0.5 g of methyl(E)-11-[2-(6-methoxy-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-62a) and 2.3g of the mixture of Compounds E-61a and E-62a.

EXAMPLE 27 Methyl(E)-11-[2-(4-phenylimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-38a) EXAMPLE 28 Methyl(E)-11-[2-(5-fluoro-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-49a) and methyl(E)-11-[2-(6-fluoro-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound E-50a) EXAMPLE 29 Methyl(E)11-[2-(5-trifluoromethyl-1-benzimidazolyl)ethylidene]-6,11-dihydrobenz[b,e]oxepin-2-carboxylate(Compound E-51a) and methyl(E)-11-[2-(6-trifluoromethyl-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-52a) EXAMPLE 30 Methyl(E)-11-[2-(5-chloro-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-53a) and methyl(E)-11-[2-(6-chloro-1-benzimidazolyl]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-54a) EXAMPLE 31 Methyl(E)-11-[2-[5-(1-phenyl-1-hydroxy)methyl-1-benzimidazolyl]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-81a) and methyl(E)-11-[2-[6-(1-phenyl-1-hydroxy)methyl-1-benzimidazolyl]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-82a) EXAMPLE 32 Methyl(E)-11-[2-(5-methoxycarbonyl-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-83a) and methyl (E)-11-[2-(6-methoxycarbonyl-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-84a)

In Examples 27 through 32, the products were prepared using Compound hand corresponding benzimidazole derivatives in a manner similar toExample 26.

EXAMPLE 33 A 1:1 mixture of methyl(E)-11-[2-(5-methyl-1-benzimidazolyl)ethylidene]-6,11dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-47a) and methyl(E)-11-[2-(6-methyl-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-48a) EXAMPLE 34 A 1:1 mixture of methyl(E)-11-[1-[5-[N-(1-hexyl)carbamoyl]-1-benzimidazolyl]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-85a) and methyl(E)-11-[2[6-[N-(1-hexyl)carbamoyl]-1-benzimidazolyl]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-86a) EXAMPLE 35 A 1:1 mixture of methyl(E)-11-[2-[5-(N-benzylcarbamoyl)-1-benzimidazolyl]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-87a) and methyl(E)-11-[2-[6-(N-benzylcarbamoyl)-1-benzimidazolyl]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-88a)

In Examples 33 through 35, the products were prepared using Compound hand corresponding benzimidazole derivatives in a manner similar toExample 26. Isolation of position isomers was not carried out.

EXAMPLE 36 Methyl(E)-11-[2-(4,5-dimethyl-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-96a) EXAMPLE 37 Methyl(E)-11-[2-(4,6-dimethyl-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-99a) EXAMPLE 38 Methyl(E)-11-[2-(4,6-dimethoxy-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-106a) EXAMPLE 39 Methyl(E)-11-[2-(5,7-dimethoxy-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-107a)

In Examples 36 through 39, the products were prepared using Compound hand corresponding benzimidazole derivatives in a similar manner toExample 26.

EXAMPLE 40 Methyl(E)-11-[2-(5,6-dimethoxy-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-89a) EXAMPLE 41 Methyl(E)-11-[2-(5,6-methylenedioxy-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-100a) EXAMPLE 42 Methyl(E)-11-[2-(5,6-dichloro-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-101a) EXAMPLE 43 Methyl(E)-11-[2-(5,6-dichloro-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-108a) EXAMPLE 44 Methyl(E)-11-[2-(1-naphtho[2,3-d]imidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-109a) EXAMPLE 45 Methyl(E)-11-[2-(4-aza-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-110a) EXAMPLE 46 Methyl (E)-11-[2-(2-methylthio-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-113a) EXAMPLE 47 Methyl(E)-11-[2-(2-methyl-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-114a) EXAMPLE 48 Methyl(E)-11-[2-(1-benzotriazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-118a) EXAMPLE 49 Methyl(E)-11-[2-(7-aza-1-indolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-121a)

In Examples 40 through 49, the products were prepared in a mannersimilar to Example 23, using Compound h and the correspondingbenzimidazole or indole derivatives.

EXAMPLE 50 Methyl(Z,E)-9-bromo-11-[2-(1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 43a)

Methyl(Z,E)-9-bromo-11-(2-chloroethylidene)-6,11dihydrodibenz[b,e]oxepin-2-carboxylate(Compound k; Z/E=1/2), 1.5 g obtained in Reference Example 11, and 1.1 gof benzimidazole were treated in a manner similar to Example 23 toprepare the objective compound (Z/E=1/2).

EXAMPLE 51 Methyl(Z)-11-[2-(5,6-dimethyl-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound Z-89a)

Methyl(Z,E)-11-(2-chloroethylidene)-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound h; Z/E=1/1), 1.1 g obtained in a similar manner to ReferenceExample 8 was reacted with 0.61 g of 5,6-dimethyl-benzimidazole in 50 mlof tetrahydrofuran in the presence of 0.17 g of 60% oily sodium hydrideat room temperature for one night. The reaction mixture was extractedwith 300 ml of ethyl acetate, and washed successively with saturatedsodium bicarbonate aqueous solution and saturated sodium chlorideaqueous solution. After drying over anhydrous magnesium sulfate, thesolvent was distilled off under reduce pressure. The resulting residuewas subjected to silica gel column chromatography (eluting solvent;hexane:ethyl acetate:triethylamine=20:20:1) to give 300 mg of thedesired product (Z-form).

EXAMPLE 52 Methyl(E)-11-[2-(5,6-dimethyl-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetate(Compound E-90a) EXAMPLE 53 Methyl(E)-11-[2-(5,6-dimethyl-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-3-carboxylate(Compound E-93a) EXAMPLE 54 Methyl(E)-11-[2-(5,6-dimethyl-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-9-carboxylate(Compound E-94a)

In Examples 52 through 54, the desired product were prepared in asimilar manner to Example 23, using Compound l, i or j obtained inReference Example 12, 9 or 10 and 5,6-dimethylbenzimidazole.

EXAMPLE 55 Methyl(Z,E)-5-[2-(1-benzimidazolyl)ethylidene]-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-3-carboxylate(Compound 172a; Z/E=7/3) EXAMPLE 56 Methyl(Z,E)-5-[2-(5,6-dimethyl-1-benzimidazolyl)ethylidene]-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-3-carboxylate(Compound 173a; Z/E=7/3) EXAMPLE 57 Methyl(Z,E)-5-[2-(1-benzimidazolyl)ethylidene]-5H-dibenzo[a,d]cyclohepten-3-carboxylate(Compound 177a; Z/E=1/1) EXAMPLE 58 Methyl(Z,E)-5-[2-(5,6-dimethyl-1-benzimidazolyl)ethylidene]-5H-dibenzo[a,d]cyclohepten-3-carboxylate(Compound 178a; Z/E=1/1) EXAMPLE 59 Methyl(Z,E)-5-[2-(5,6-dimethyl-1-benzimidazolyl)ethylidene]-5H-dibenzo[a,b]cyclohepten-3-acetate(Compound 179a; Z/E=11/9)

In Examples 55 through 59, the products were prepared in a similarmanner to Example 23 using Compound r, t or u obtained in ReferenceExample 18, 20 or 21 and corresponding benzimidazole derivatives.

The physicochemical properties of the compounds obtained in Examples 23through 59 are shown in Table 5-3.

                                      TABLE 5-3                                   __________________________________________________________________________    Example   MP °C.                                                       No.       (Solvent                                                            (Com-     for                 IR                                              pound                                                                              Appear-                                                                            recrystal-                                                                         NMR            (Method)                                                                            Elemental analysis                        No.) ance lization)                                                                          (Solvent) δ, ppm                                                                       cm.sup.-1                                                                           %                                         __________________________________________________________________________    23   yellow                                                                             --   (CDCl.sub.3) 3.82(s, 3H), 4.60                                                               (CHCl.sub.3)                                                                        --                                        (37a)                                                                              amor-     (d, J=7.6Hz, 2H), 4.55-5.56                                                                  2950, 1713,                                          phous     (b, 2H), 6.17(t, J=7.2Hz, 1H),                                                               1609, 1296,                                                    6.66-8.04(m, 10H)                                                                            1121, 1005                                      24   pale unclear                                                                            (CDCl.sub.3) 3.86(s, 3H), 4.86                                                               --    --                                        (E-41a)                                                                            yellow    (d, J=7.2Hz, 2H), 4.72-5.54                                         amor-     (b, 2H), 6.24(t, J=7.2Hz, 1H),                                      phous     6.69-8.21(m, 11H), 7.83(s,                                                    1H)                                                            25   pale --   (CDCl.sub.3) 3.87(s, 3H), 4.97                                                               --    --                                        (E-55a)                                                                            yellow    (d, J=7.0Hz, 2H), 4.80-5.45                                         oil       (b, 2H), 6.25(t, J=7.0Hz, 1H),                                                6.64-8.29(m, 10H), 8.58(d, J=                                                 1.8Hz, 1H)                                                     25   pale --   (DMSO-d.sub.6) 3.78(s, 3H), 4.80-                                                            --    --                                        (E-56a)                                                                            yellow    5.50(m, 4H), 6.31T, J=7.0                                           oil       Hz, 1H), 6.75-8.08(m, 10H),                                                   8.55(s, 1H)                                                    26   white                                                                              99-101                                                                             (CDCl.sub.3) 3.84(s, 3H), 3.87                                                               (KBr  --                                        (E-61a)                                                                            crystal                                                                            (toluene)                                                                          (s, 3H), 4.7-5.6(m, 4H), 4.88                                                                tablet)                                                        (d, J=7.3Hz, 2H), 6.28(t, J=                                                                 3400, 2948,                                                    7.3Hz, 1H), 6.75-8.00(m, 11H)                                                                1714, 1606,                                                                   1492, 1436,                                                                   1228, 1119,                                                                   837, 767                                        26   white                                                                              179-180                                                                            (CDCl.sub.3) 3.80(s, 3H), 3.88(s,                                                            (KBr  --                                        (E-62a)                                                                            crystal                                                                            (aceto-                                                                            3H), 4.7-5.7(m, 4H), 4.87(d,                                                                 tablet)                                                   nitrile)                                                                           J=71.Hz, 2H), 6.29(t, J=7.1                                                                  3450, 1717,                                                    Hz, 1H), 6.54(d, J=2.2Hz, 1H),                                                               1505, 1485,                                                    6.72-8.01(m, 10H)                                                                            1249, 1004,                                                                   818, 767                                        27   color-                                                                             --   (CDCl.sub.3) 3.88(s, 3H), 4.70(d,                                                            (CHCH.sub.3)                                                                        [MS(m/z): 422(M.sup.+)]                   (E-38a)                                                                            less      J=7.0Hz, 2H), 4.8-5.6(b, 2H),                                                                1709, 1606,                                          amor-     6.30(t, J=7.0Hz, 1H), 6.82(d,                                                                1485, 1435,                                          phous     J=8.6Hz, 1H), 7.14(d, J=1.5                                                                  1244, 1118,                                                    Hz, 1H), 7.1-7.5(m, 9H), 7.70                                                                1002                                                           (d, J=1.5Hz, 1H), 7.83(dd, J=                                                 2.2&8.5Hz, 1H), 8.01(d, J=                                                    2.2Hz, 1H)                                                     28   color-                                                                             --   (CDCl.sub.3) 3.87(s, 3H), 4.93(d,                                                            --    [MS(m/z): 414(M.sup.+)]                   (E-49a)                                                                            less      J=7.0Hz, 2H), 4.9-6.5(b, 2H),                                       amor-     6.28(t, J=7.0Hz, 1H), 6.80(d,                                       phous     J=8.5Hz, 1H), 6.85-7.05(m,                                                    2H), 7.2-7.5(m, 5H), 7.81                                                     (dd, J=2.0&8.5Hz, 1H), 7.93                                                   (s, 1H), 7.98(d, J=2.0Hz, 1H)                                  28   color-                                                                             --   (CDCl.sub.3) 3.87(s, 3H), 4.89(d,                                                            --    [MS(m/z): 414(M.sup.+)]                   (E-50a)                                                                            less      J=7.0Hz, 2H), 5.0-6.5(b, 2H),                                       amor-     6.25(t, J=7.0Hz, 1H), 6.55-                                         phous     6.70(m, 1H), 6.80(d, J=8.5Hz,                                                 1H), 6.85-7.10(m, 1H), 7.2-                                                   7.7(m, 5H), 7.81(dd, J=2.0&                                                   8.5Hz, 1H), 7.88(s, 1H), 8.00                                                 (d, J=2.0Hz, 1H)                                               29   color-                                                                             --   (CDCl.sub.3) 3.85(s, 3H), 4.90(d,                                                            (CHCl.sub.3)                                                                        [MS(m/z): 464(M.sup.+)]                   (E-51a)                                                                            less      J=7.0Hz, 2H), 4.8- 5.6(b, 2H),                                                               1712, 1608,                                          oil       6.24(t, J=7.0Hz, 1H), 6.80(d,                                                                1328, 1251,                                                    J=8.5Hz, 1H), 7.0-8.3(m, 10H)                                                                1166, 1112                                                                    995                                             29   color-                                                                             --   (CDCl.sub.3) 3.85(s, 3H), 4.88(d,                                                            (CHCl.sub.3)                                                                        [MS(m/z): 464(M.sup.+)]                   (E-52a)                                                                            less      J=7.0Hz, 2H), 4.8-5.6(b, 2H)                                                                 1712, 1607,                                          oil       6.25(t, J=7.0Hz, 1H), 6.78(d,                                                                1344, 1243,                                                    J=8.5Hz, 1H), 7.1-8.1(m, 10H)                                                                1162, 1005                                      30   color-                                                                             --   (CDCl.sub.3) 3.87(s, 3H), 4.90(d,                                                            --    [MS(m/z): 430(M.sup.+)]                   (E-53a)                                                                            less      J=7.0Hz, 2H), 4.5-5.6(b, 2H),                                       oil       6.26(t, J=7.0Hz, 1H), 6.80(d,                                                 J=8.5Hz, 1H), 6.91-7.90(m,                                                    9H), 7.99(d, J=2.2Hz, 1H)                                      30   color-                                                                             --   (CDCl.sub.3) 3.87(s, 3H), 4.89(d,                                                            --    [MS(m/z): 430(M.sup.+)]                   (E-54a)                                                                            less      J=7.0Hz, 2H), 4.5-5.7(b, 2H),                                       oil       6.22(t, J=7.0Hz, 1H), 6.80(d,                                                 J=8.6Hz, 1H), 6.91(d, J=1.3                                                   Hz, 1H), 7.10-7.87(m, 7H),                                                    7.83(s, 1H), 7.99(d, J=2.2Hz,                                                 1H)                                                            31   color-                                                                             --   (CDCl.sub.3) 3.87(s, 3H), 4.91(d,                                                            --    [MS(m/z): 502(M.sup.+)]                   (E-81a)                                                                            less      J=7.0Hz, 2H), 4.5-5.6(b, 2H),                                       oil       5.92(s, 1H), 6.7-8.0(m, 16H)                                   31   color-                                                                             --   --             --    [MS(m/z): 502(M.sup.+)]                   (E-82a)                                                                            less                                                                          oil                                                                      32   color-                                                                             --   (CDCl.sub.3) 3.87&3.93(each s,                                                               (CHCl.sub.3)                                                                        [MS(m/z): 454(M.sup.+)]                   (E-83a)                                                                            less      6H), 4.95(d, J=7.1Hz, 2H),                                                                   1711                                                 oil       4.6-5.7(b, 2H), 6.29(t, J=7.1                                                 Hz, 1H), 6.80(d, J=8.6Hz, 1H),                                                7.07(d, J=8.6Hz, 1H), 7.26-                                                   7.52(m, 5H), 7.81(dd, J=2.2&                                                  8.6Hz, 1H), 7.90(s, 1H), 8.00                                                 (d, J=2.2Hz, 1H), 8.50(d, J=                                                  1.4Hz, 1H)                                                     32   white                                                                              231-232                                                                            (CDCl.sub.3) 3.87&3.95(each s,                                                               (KBr  C.sub.27 H.sub.22 N.sub.2 O.sub.5         (E-84a)                                                                            crystal                                                                            (toluene)                                                                          6H), 4.99(d, J=7.0Hz, 2H),                                                                   tablet)   C  H  N                                              4.5-5.8(b, 2H), 6.23(t, J=7.0                                                                1712, 1282,                                                                         Found                                                                             71.42                                                                            4.91                                                                             6.25                                           Hz, 1H), 6.80(d, J=8.6Hz, 1H),                                                               1250, 1131,                                                                         Calcd.                                                                            71.35                                                                            4.88                                                                             6.16                                           7.25-8.01(m, 10H)                                                                            1004                                            33   color-                                                                             --   (CDCl.sub.3) 2.37(s, 1.5H), 2.41                                                             --    [MS(m/z): 410(M.sup.+)]                   (mixture                                                                           less      (s, 1.5H), 3.86(s, 3H), 4.84                                   of E-47a                                                                           oil       (d, J=7.2Hz, 2H), 4.58-5.57                                    and            (b, 2H), 6.23(t, J=7.2Hz, 1H),                                 E-48a)         6.78-7.50(m, 8H), 7.76(s, 1H),                                                7.79(dd, J=2.0&8.6Hz, 1H),                                                    7.98(d, J=2.0Hz, 1H)                                           34   color-                                                                             --   (CDCl.sub.3) 0.75-1.90(m, 11H),                                                              (neat)                                                                              [MS(m/z): 523(M.sup.+)]                   (mixture                                                                           less      3.35-3.70(m, 2H), 3.87(s,                                                                    1715, 1246,                                     of E-85a                                                                           oil       3H), 4.97(d, J=7.3Hz, 2H),                                                                   1002                                            and            4.8-5.3(b, 2H), 6.0-6.4(m,                                     E-86a)         1H), 6.80(d, J=8.6Hz, 1H),                                                    7.0-8.40(m, 11H)                                               35   color-                                                                             --   (CDCl.sub.3) 3.86(s, 3H), 4.3-                                                               (neat)                                                                              [MS(m/z): 529(M.sup.+)]                   (mixture                                                                           less      5.7(b, 2H), 4.68(d, J=5.7Hz,                                                                 1704, 1118,                                     of E-87a                                                                           oil       2H), 4.89-5.00(m, 2H), 6.14-                                                                 1002                                            and            6.31(m, 1H), 6.3-8.17(m,                                       E-88a)         11H)                                                           36   color-                                                                             --   (CDCl.sub.3) 2.37(s, 3H), 2.57(s,                                                            --    [MS(m/z): 424(M.sup.+)]                   (E-96a)                                                                            less      3H), 3.86(s, 3H), 4.86(d, J=                                        oil       7.0Hz, 2H), 4.68-5.57(b, 2H),                                                 6.25(t, J=7.2Hz, 1H), 6.68-                                                   7.50(m, 7H), 7.76(s, 1H),                                                     7.79(dd, J=2.2&8.6Hz, 1H),                                                    7.98(d, J=2.2Hz, 1H)                                           37   color-                                                                             --   (CDCl.sub.3) 2.37(s, 3H), 2.59(s,                                                            --    [MS(m/z): 424(M.sup.+)]                   (E-99a)                                                                            less      3H), 3.86(s, 3H), 4.84(d, J=                                        oil       7.3Hz, 2H), 4.50-5.56(b, 2H),                                                 6.23(t, J=7.2Hz, 1H), 6.55-                                                   6.90(m, 2H), 7.15-7.50(m,                                                     5H), 7.74(s, 1H), 7.72-7.85                                                   (m, 1H), 7.89-8.01(m, 1H)                                      38   color-                                                                             --   (CDCl.sub.3) 3.77(s, 3H), 3.88(s,                                                            (neat)                                                                              [MS(m/z): 456(M.sup.+)]                   (E-106a)                                                                           less      3H), 3.98(s, 3H), 4.84(d, J=                                                                 1716, 1607,                                          oil       7.0Hz, 2H), 4.6-5.6(b, 2H),                                                                  1437, 1248,                                                    6.1-6.4(m, 2H), 6.80(d, J=                                                                   1153, 1005                                                     8.8Hz, 1H), 7.2-7.5(m, 4H),                                                   7.62(s, 1H), 7.83(dd, J=2.0&                                                  8.8Hz, 1H), 8.00(d, J=2.0Hz,                                                  1H)                                                            39   color-                                                                             --   (CDCl.sub.3) 3.80(s, 3H), 3.83(s,                                                            (neat)                                                                              [MS(m/z): 456(M.sup.+)]                   (E-107a)                                                                           less      3H), 3.87(s, 3H), 5.10(d, J=                                                                 1713, 1603,                                          oil       6.8Hz, 2H), 4.8-5.6(b, 2H),                                                                  1304, 1246,                                                    6.2-7.5(m, 8H), 7.77(dd, J=                                                                  1148, 1117,                                                    1.8&8.5Hz, 1H), 7.99(d, J=                                                                   999                                                            1.8Hz, 1H)                                                     40   white                                                                              --   (CDCl.sub.3) 2.32(bs, 6H), 3.89                                                              (KBr  --                                        (E-89a)                                                                            amor-     (s, 3H), 4.82(d, J=7.0Hz, 2H),                                                               tablet)                                              phous     4.67-5.71(b, 2H), 6.25(t, J=                                                                 2924, 1720,                                                    7.0Hz, 1H), 6.71-8.11(m, 10H)                                                                1607, 1489,                                                                   1293, 1232,                                                                   1003                                            41   color-                                                                             --   (CDCl.sub.3) 3.87(s, 3H), 4.86(d,                                                            (neat)                                                                              [MS(m/z): 440(M.sup.+)]                   (E-100a)                                                                           less      J=7.0Hz, 2H), 4.6-5.6(b, 2H),                                                                1711, 1606,                                          oil       5.96(s, 2H), 6.25(t, J=7.0Hz,                                                                1464, 1228,                                                    2H), 6.46(s, 1H), 6.80(d, J=                                                                 1114, 1004                                                     8.6Hz, 1H), 7.17-7.51(m, 5H),                                                 7.82(dd, J=2.0&8.6Hz, 1H),                                                    7.84(s, 1H), 7.99(d, J=2.0Hz,                                                 1H)                                                            42   pale --   (CDCl.sub.3) 3.84(s, 3H), 3.87(s,                                                            --    --                                        (E-101a)                                                                           yellow    3H), 3.92(s, 3H), 4.87(d, J=                                        oil       7.0Hz, 2H), 4.80-5.50(b, 2H),                                                 6.30(t, J=7.0Hz, 1H), 6.53(s,                                                 1H), 6.80(d, J=8.6Hz, 1H),                                                    7.26-8.02(m, 8H)                                               43   pale --   (CDCl.sub.3) 3.88(s, 3H), 4.7-5.5                                                            (neat)                                                                              --                                        (E-108a)                                                                           yellow    (b, 2H), 4.89(d, J=7.3Hz, 1H),                                                               2878, 1711,                                          oil       6.21(t, J=7.3Hz, 1H), 6.80(d,                                                                1607, 1488,                                                    J=8.6Hz, 1H), 7.00(s, 1H),                                                                   1313, 1246,                                                    7.19-8.00(m, 8H)                                                                             1118, 1004                                      44   color-                                                                             --   (CDCl.sub.3) 3.81(s, 3H), 4.88(d,                                                            --    --                                        (E-109a)                                                                           less      J=7.0Hz, 2H), 4.75-5.56(b,                                          oil       2H), 6.28(t, J=7.0Hz, 1H),                                                    6.67-8.26(m, 14H)                                              45   color-                                                                             --   (CDCl.sub.3) 3.84(s, 3H), 4.7-5.7                                                            --    --                                        (E-110a)                                                                           less      (m, 4H), 6.36(t, J=6.9Hz, 1H),                                      oil       6.80(d, J=8.6Hz, 1H), 7.1-7.5                                                 (m, 5H), 7.81(dd, J=2.2&8.6                                                   Hz, 1H), 7.92(s, 1H), 8.01(d,                                                 J=2.2Hz, 1H), 8.09(bs, 1H),                                                   8.39(dd, J=1.3, 4.8Hz, 1H)                                     46   pale --   (CDCl.sub.3) 2.76(s, 3H), 3.87(s,                                                            (KBr  --                                        (E-113a)                                                                           yellow    3H), 4.7-5.7(m, 4H), 6.12(t,                                                                 tablet)                                              oil       J=6.8Hz, 1H), 6.77(d, J=8.6Hz,                                                               2926, 1607,                                                    1H), 6.85-7.70(m, 8H), 7.78                                                                  1435, 1246,                                                    (dd, J=2.2&8.6Hz, 1H), 7.99                                                                  1118, 1005                                                     (d, J=2.2Hz, 1H)                                               47   color-                                                                             --   (CDCl.sub.3) 2.41(s, 3H), 3.85(s,                                                            (KBr  --                                        (E-114a)                                                                           less      3H), 4.78(d, J=7.2Hz, 2H),                                                                   tablet)                                              amor-     4.60-5.64(b, 2H), 6.06(t, J=                                                                 2924, 1711,                                          phous     7.2Hz, 1H), 6.63-7.98(m, 11H)                                                                1606, 1401,                                                                   1245, 1118,                                                                   1005                                            48   color-                                                                             --   (CDCl.sub.3) 3.84(s, 3H), 4.82-                                                              --    --                                             less      5.69(m, 4H), 6.36(t, J=5.4Hz,                                       oil       1H), 7.19-8.6(m, 11H)                                          49   yellow                                                                             --   (CDCl.sub.3) 3.80(s, 3H), 4.79-                                                              --    --                                        (E-121a)                                                                           amor-     5.78(m, 4H), 6.38(t, J=6.8Hz,                                       phous     1H), 6.51-6.88(m, 2H), 7.13-                                                  7.48(m, 5H), 7.61-8.16(m, 5H)                                  50   color-                                                                             --   (CDCl.sub.3) 3.87(s, 3H), 4.87(d,                                                            --    --                                        (43a)                                                                              less      J=7.0Hz, 2H), 4.77-5.63(b,                                          oil       2H), 6.25(t, J=7.0Hz, 1H),                                                    6.82-8.07(m, 10H)                                              51   color-                                                                             --   (CDCl.sub.3) 2.36(s, 6H), 3.89(s,                                                            (CHCl.sub.3)                                                                        [MS(m/z): 424(M.sup.+)]                   (Z-89a)                                                                            less      3H)            1714, 1610,                                          oil                      1487, 1245,                                                                   1126, 999                                       52   color-                                                                             --   (CDCl.sub.3) 2.33(bs, 6H), 3.51                                                              (neat)                                                                              [MS(m/z): 438(M.sup.+)]                   (E-90a)                                                                            less      (s, 2H), 3.65(s, 3H), 4.90(d,                                                                1738, 1493,                                          oil       J=7.5Hz, 2H), 5.20(bs, 2H),                                                                  1223, 1160,                                                    6.18(t, J=7.5Hz, 1H), 6.67-                                                                  1001                                                           7.55(m, 9H), 7.99(s, 1H)                                       53   color                                                                              --   (CDCl.sub.3) 2.32&2.35(each s,                                                               (neat)                                                                              [MS(m/z): 424(M.sup.+)]                   (E-93a)                                                                            less      6H), 3.86(s, 3H), 4.86(d, J=                                                                 1715, 1489                                           oil       7.1Hz, 2H), 5.22(bs, 2H),                                                                    1096, 1027                                                     6.23(t, J=7.1Hz, 1H), 6.80(s,                                                 1H), 7.25-7.56(m, 8H), 7.72                                                   (s, 1H)                                                        54   white                                                                              202-203                                                                            (CDCl.sub.3) 2.33(s, 6H), 3.93(s,                                                            (KBr  C.sub.27 H.sub.24 N.sub.2 O.sub.3         (E-94a)                                                                            crystal                                                                            (aceto-                                                                            3H), 4.86(d, J=7.0Hz, 2H),                                                                   tablet)   C  H  N                                         nitrile)                                                                           5.22(bs, 2H), 6.22(t, J=7.0                                                                  1721, 1435,                                                                         Found                                                                             76.42                                                                            5.88                                                                             6.51                                           Hz, 1H), 6.65-8.15(m, 10H)                                                                   1288, 1262,                                                                         Calcd.                                                                            76.39                                                                            5.70                                                                             6.60                                                          1215, 1009                                      55   pale --   (CDCl.sub.3) 2.73-3.48(m, 4H),                                                               --    --                                        (172a)                                                                             yellow    3.88(s, 1H), 3.90(s, 2H),                                           oil       4.82-4.89(m, 2H), 6.09(t, J=                                                  7.0Hz, 0.7H; Z form), 6.12                                                    (t, J=6.9Hz, 0.3H; E form),                                                   6.98-7.45(m, 8H), 7.70-8.03                                                   (m, 4H)                                                        56   pale --   (CDCl.sub.3) 2.34(s, 6H), 2.80-                                                              --    --                                        (173a)                                                                             yellow    3.45(m, 4H), 3.89(s, 1H),                                           oil       3.91(s, 2H), 4.77-4.85(m,                                                     2H), 6.07(t, J=7.0Hz, 0.7H;                                                   Z form), 6.08(t, J=7.1Hz,                                                     0.3H; E form), 6.91-8.04(m,                                                   10H)                                                           57   pale --   (CDCl.sub.3) 3.91(s, 1.5H), 3.93                                                             --    --                                        (177a)                                                                             yellow    (s, 1.5H), 4.77(dd, J=2.6&                                          oil       8.8Hz, 1H), 4.85(dd, J=2.6&                                                   5.5Hz, 1H), 5.73(dd, J=1.3&                                                   5.4Hz, 0.5H), 5.82(dd, J=1.6                                                  &5.1Hz, 0.5H), 6.81-8.07                                                      (m, 14H)                                                       58   pale --   (CDCl.sub.3) 2.32(s, 6H), 3.91(s,                                                            --    --                                        (178a)                                                                             yellow    1.5H), 4.66-4.84(m, 2H),                                            oil       5.66-5.82(m, 1H), 6.89(bs,                                                    2H), 6.95-8.08(m, 10H)                                         59   pale --   (CDCl.sub.3) 2.32(s, 6H), 3.61(s,                                                            --    [MS(m/z): 434(M.sup.+)]                   (179a)                                                                             yellow    2H), 3.65&3.66(each s, 1H),                                         oil       4.67-4.83(m, 2H), 5.70(dd,                                                    J=5.5&8.4Hz, 1H), 6.91(bs,                                                    2H), 7.00-7.48(m, 9H), 7.70                                                   &7.73(each s, 1H)                                              __________________________________________________________________________

EXAMPLE 60(Z)-11-[2-(1-Imidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]-oxepin-2-carboxylicacid (Compound Z-37b) and(E)-11-[2-(1-imidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid 0.2 hydrate (Compound E-37b')

Compound 37a, 5.9 g, obtained in Example 23 was hydrolyzed in a mannersimilar to Example 14 to give a mixture (Z/E=1/9) of crude CompoundsZ-37b and E-37b.

The mixture was repeatedly washed with hot methanol to give 1.7 g of(E)-11-[2-(1-imidazolyl)ethylidene-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid 0.2 hydrate (Compound E-37b').

The washing liquid was concentrated and then allowed to stand at roomtemperature. The precipitated crystals were taken by filtration to give0.1 g of(Z)-11-[2-(1-imidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound E-37b).

EXAMPLE 61(E)-11-[2-(1-Benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound E-41b)

Compound E-41a, 12.9 g, obtained in Example 24 was hydrolyzed in amanner similar to Example 15 to give a crude product.

The resulting crude product was recrystallized from isopropanol and thenwashed with hot methanol to give 10.0 g of the product.

EXAMPLE 62 Sodium(E)-11-[2-(1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate0.6 ethanol 0.6 hydrate (Compound E-41b')

Compound E-41b, 59.4 g, obtained in Example 61 was suspended in 1.5 l ofmethanol and 29.9 g of 28% sodium methoxide/methanol solution was addedto the suspension followed by stirring at room temperature for 2 hours.The solvent was distilled off under reduced pressure. The resultingresidue was recrystallized from 30 ml of water and 1.2 l of acetone. Thecrystals were taken by filtration to give a crude product. The crudeproduct was washed with hot methanol to give 64.5 g of the product.

EXAMPLE 63(E)-11-[2-(4-Phenyl-1-imidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound E-38b) EXAMPLE 64(Z,E)-9-Bromo-11-[2-(1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid monohydrate (Compound 43b', Z/E=1/2) EXAMPLE 65(E)-11-[2-(5-Fluoro-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound E-49b) EXAMPLE 66(E)-11-[2-(6-Fluoro-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound E-50b) EXAMPLE 67(E)-11-[2-(5-Trifluoromethyl-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid·0.5 isopropanol (Compound E-51b' ) EXAMPLE 68(E)-11-[2-(6-Trifluoromethyl-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound E-52b) EXAMPLE 69(E)-11-[2-(5-Chloro-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid·0.5 hydrate (Compound E-53b') EXAMPLE 70(E)-11-[2-(6-Chloro-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid·0.25 hydrate (Compound E-54b') EXAMPLE 71(E)-11-[2-(5-Nitro-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid·0.2 hydrate (Compound E-55b') EXAMPLE 72(E)-11-[2-(6-Nitro-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound E-56b) EXAMPLE 73(E)-11-[2-(5-Methoxy-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound E-61b) EXAMPLE 74(E)-11-[2-(6-Methoxy-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound E-62b) EXAMPLE 75(E)-11-[2-[5-(1-Phenyl-1-hydroxy)methyl-1-benzimidazolyl]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid·monohydrate (Compound E-81b') EXAMPLE 76(E)-11-[2-[6-(1-phenyl-1-hydroxy)methyl-1-benzimidazolyl]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid·1.5 hydrate (Compound E-82b') EXAMPLE 77 (E)-11[-2-(5-Carboxy-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid·0.25 hydrate (Compound E-83b') EXAMPLE 78(E)-11-[2-(6-Carboxy-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid (Compound E-84b) EXAMPLE 79(E)-11-[2-(5,6-Dimethyl-1-benzimidazoly)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid·0.25 hydrate (Compound E-89b')

In Examples 63 through 79, the products were prepared by hydrolyzingesters of the corresponding oxepine derivative in a manner similar toExample 14 or 15.

EXAMPLE 80(E)-11-[2-(5,6-Dimethyl-1-benzimidazoly)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid·monohydrochloride·1 isopropanol (Compound E-89b")

Compound E-89b', 0.5 g, obtained in Example 79 was treated in a mannersimilar to Example 3 to give 0.5 g of the product.

EXAMPLE 81 Sodium(E)-11-[2-(5,6-Dimethyl-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate·monohydrate(Compound E-89b"')

Compound E89b', 0.5 g, obtained in Example 79 was treated in a mannersimilar to Example 62 to give 0.3 g of the product.

EXAMPLE 82(Z)-11-[2-(5,6-Dimethyl-1-Benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound Z-89b) EXAMPLE 83(E)-11-[2-(5,6-Dimethyl-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-aceticacid (Compound E-90b) EXAMPLE 84(E)-11-[2-(5,6-Dimethyl-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-3-carboxylicacid·0.5 isopropanol (Compound E-93b') EXAMPLE 85(E)-11-[2(5,6-Dimethyl-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-9-carboxylicacid·0.25 hydrate (Compound E-94b') EXAMPLE 86(E)-11-[2-(4,5-Dimethyl-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound E-96b) EXAMPLE 87(E)-11-[2-(4,6-Dimethyl-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid·0.3 isopropanol (Compound E-99b') EXAMPLE 88(E)-11-[1-(5,6-Methylenedioxy-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid 0.5 hydrate (Compound E100b') EXAMPLE 89(E)-11-[2-(5,6-Dimethoxy-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound E-101b) EXAMPLE 90(E)-11-[2-(4,6-Dimethoxy-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid·0.25 hydrate (Compound E-106b') EXAMPLE 91(E)-11-[2-(5,7-Dimethoxy-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound E-107b) EXAMPLE 92(E)-11-[2-(5,6-Dichloro-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid·0.5 acetonitrile ·0.25 hydrate (Compound E-108b') EXAMPLE 93(E)-11-[2-(1-Naphtho[2,3-d]imidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid·0.5 N,N-dimethylformamide ·0.25 hydrate (Compound E-109b') EXAMPLE94(E)-11-[2-(4-Aza-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound E-110b) EXAMPLE 95(E)-11-[2-(2-Methylthio-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid·0.25 hydrate (Compound E-113b') EXAMPLE 96(E)-11-[2-(2-Methyl-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound E-114b) EXAMPLE 97(E)-11-[2-(1-Benzotriazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound E-118b) EXAMPLE 98(E)-11-[2-(7-Aza-1-indolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid 1.4 hydrate (Compound E-121b')

In Examples 82 through 98, the products were prepared by hydrolyzingesters of the corresponding oxepine derivatives in a manner similar toExample 14 or 15.

EXAMPLE 99 A 1:1 mixture of(E)-11-[2-(5-methyl-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound E-47b) and(E)-11-[2-(6-methyl-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound E-48b) EXAMPLE 100 A 81:19 mixture·0.6 isopropanol of(E)-11-[2-[5-[N-(1-hexyl)carbamoyl]-1-benzimidazolyl]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound E-85b') and(E)-11-[2-[6-[N-(1-hexyl)carbamoyl]-1-benzimidazolyl]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound E-86b') 101 A 57:43 mixture of(E)-11-[2-[5-(N-benzylcarbamoyl)-1-benzimidazolyl]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound E-87b) and(E)-11-[2-[6-(N-benzylcarbamoyl)-1-benzimidazolyl]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound E-88b)

In Examples 99 through 101, the products were prepared by hydrolyzingesters of the corresponding oxepine derivatives which is a mixture ofposition isomers in a manner similar to Example 14 or 15.

EXAMPLE 102(Z)-5-[2-(1-Benzimidazolyl)ethylidene]-10,11-dihydro-5H-dibenz[a,d]cyclohepten-3-carboxylicacid (Compound Z-172b) EXAMPLE 103(E)-5-[2-(5,6-Dimethyl-1-benzimidazolyl)ethylidene-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-3-carboxylic acid (CompoundE-173b) and (Z)-5-[2-(5,6-Dimethyl-1-benzimidazolyl)ethylidene-10,11-dihydro-5H-dibenz]a,d]cyclohepten-3-carboxylic acid (CompoundZ-173b) EXAMPLE 104(Z,E)-5-[2-(1-Benzimidazolyl)ethylidene]-5H-dibenzo[a,d]-cyclohepten-3-carboxylicacid (Compound 177b; Z/E=1/1) EXAMPLE 105(E)-5-[2-(5,6-Dimethyl-1-benzimidazolyl)ethylidene]-5H-dibenzo[a,d]cyclohepten-3-carboxylicacid·0.3 isopropanol (Compound E-178b') EXAMPLE 106(E)-5-[2-(5,6-Dimethyl-1-benzimidazolyl)ethylidene]-5H-dibenzo[a,d]cyclohepten-3-aceticacid·0.2 hydrate (Compound E-179b')

In Examples 102 through 106, the products were prepared by hydrolyzingesters of corresponding cyclohepten derivatives in a manner similar toExample 14 or 15 and if possible isolating Z-form from E-form of isomersby recrystallization.

Physicochemical properties of the compounds obtained in Examples 60through 106 are shown in Table 5-4.

                                      TABLE 5-4                                   __________________________________________________________________________    Example   MP °C.                                                       No.       (Solvent                                                            (Com-     for                 IR                                              pound                                                                              Appear-                                                                            recrystal-                                                                         NMR            (Method)                                                                             Elemental analysis                       No.) ance lization)                                                                          (Solvent) δ, ppm                                                                       cm.sup.-1                                                                            %                                        __________________________________________________________________________    60   white                                                                              284-285                                                                            (DMSO-d.sub.6) 4.99(d, J=6.8Hz,                                                              (KBr   C.sub.20 H.sub.16 N.sub.2 O.sub.3        (Z-37b)                                                                            flossy                                                                             (dec.)                                                                             2H), 5.33(bs, 2H), 5.85(t,                                                                   tablet)    C  H  N                                        (meth-                                                                             J=6.8Hz, 1H), 6.95(d, J=8.6                                                                  3118, 1690,                                                                          Found                                                                             72.14                                                                            4.84                                                                             8.37                                     anol)                                                                              Hz, 1H), 6.96(bs, 1H), 7.31-                                                                 1605, 1288,                                                                          Calcd.                                                                            72.28                                                                            4.85                                                                             8.43                                          7.47(m, 5H), 7.73-7.82(m,                                                                    1245, 1099,                                                    2H), 7.83(bs, 1H)                                                                            1001                                            60   white                                                                              264-265                                                                            (DMSO-d.sub.6) 4.50-5.70(m, 4H),                                                             (KBr   C.sub.20 H.sub.16 O.sub.3.0.2H.sub.2                                          O                                        (E-37b')                                                                           crystal                                                                            (dec.)                                                                             6.23(t, J=7.0Hz, 1H), 6.84(d,                                                                tablet)    C  H  N                                        (meth-                                                                             J=8.6Hz, 1H), 6.92(bs, 1H),                                                                  3120, 2336,                                                                          Found                                                                             71.41                                                                            4.90                                                                             8.15                                     anol)                                                                              7.17(bs, 1H), 7.35-7.59(m,                                                                   1695, 1603,                                                                          Calcd.                                                                            71.50                                                                            4.92                                                                             8.34                                          4H), 7.63(bs, 1H), 7.73(dd,                                                                  1455,  827                                                     J=2.2, 8.6Hz, 1H), 7.92(d, J=                                                 2.2Hz, 1H)                                                     61   white                                                                              249-252                                                                            (DMSO-d.sub.6) 4.6-5.6(m, 4H),                                                               (KBr   C.sub.24 H.sub.18 N.sub.2 O.sub.3        (E-41b)                                                                            crystal                                                                            (isopro-                                                                           6.28(t, J=7.0Hz, 1H), 6.81(d,                                                                tablet)    C  H  N                                        panol)                                                                             J=8.6Hz, 1H), 7.14-7.78(m,                                                                   1685, 1606,                                                                          Found                                                                             75.35                                                                            4.62                                                                             7.37                                          9H), 7.95(d, J=2.2Hz, 1H),                                                                   1487, 1249,                                                                          Calcd.                                                                            75.38                                                                            4.74                                                                             7.33                                          8.18(s, 1H)    1004,  773,                                                                    744                                            62   white                                                                              >250   --             --   C.sub.14 H.sub.17 N.sub.2 O.sub.3                                             Na.                                      (E-41b')                                                                           crystal                                                                            (unclear)                  0.6C.sub.2 H.sub.5 OH.0.6H.sub.2 O                 (acetone-                      C  H  N                                        water)                     Found                                                                             68.28                                                                            4.89                                                                             6.15                                                                Calcd.                                                                            68.35                                                                            4.96                                                                             6.33                           63   white                                                                              275-276                                                                            (DMSO-d.sub.6) 4.5-5.8(m, 4H),                                                               (KBr tablet)                                                                         C.sub.26 H.sub.20 N.sub.2 O.sub.3        (E-38b)                                                                            crystal                                                                            (isopro-                                                                           6.30(t, J=6.8Hz, 1H), 6.85(d,                                                                1608, 1486,                                                                              C  H  N                                        panol)                                                                             J=8.5Hz, 1H), 7.14-7.78(m,                                                                   1247, 1004                                                                           Found                                                                             76.40                                                                            4.66                                                                             6.92                                          12H), 7.95(d, J=1.9Hz, 1H)                                                                          Calcd.                                                                            76.45                                                                            4.94                                                                             6.86                           64   white                                                                              262-265                                                                            (DMSO-d.sub.6) 4.75-5.60(m, 4H),                                                               --   C.sub.24 H.sub.17 BrN.sub.2 O.sub.3.H                                         .sub.2 O                                 (43b')                                                                             crystal                                                                            (dec.)                                                                             6.30(t, J=6.6Hz, 1H), 6.82(d,                                                                           C  H  N                                        (isopro-                                                                           J=8.5Hz, 1H), 7.16-7.87(m,                                                                          Found                                                                             60.17                                                                            3.67                                                                             5.72                                     panol)                                                                             8H), 7.93(d, J=2.2Hz, 1H),                                                                          Calcd.                                                                            60.14                                                                            3.99                                                                             5.84                                          8.22(s, 1H)                                                    65   white                                                                              174-177                                                                            (DMSO-d.sub.6) 4.8-5.6(m, 4H),                                                               (KBr tablet)                                                                         C.sub.24 H.sub.17 FN.sub.2 O.sub.3       (E-49b)                                                                            crystal                                                                            (isopro-                                                                           6.30(t, J=6.8Hz, 1H), 6.83(d,                                                                1690, 1606,                                                                              C  H  N                                        panol)                                                                             J=8.5Hz, 1H), 7.08(dt, J=                                                                    1487, 1243                                                                           Found                                                                             72.03                                                                            4.48                                                                             7.00                                          9.3 & 2.2Hz, 1H), 7.23(dd, J=                                                                       Calcd.                                                                            71.99                                                                            4.28                                                                             7.00                                          4.7 & 9.0Hz, 1H), 7.40-7.56(m,                                                4H), 7.57-7.62(m, 1H), 7.72                                                   (dd, J=2.2 & 8.5Hz, 1H), 7.94                                                 (d, J=2.2Hz, 1H), 8.26(s, 1H)                                  66   white                                                                              287-288                                                                            (DMSO-d.sub.6) 4.7-5.6(m, 4H),                                                               (KBr tablet)                                                                         C.sub.24 H.sub.17 FN.sub.2 O.sub.3       (E-50b)                                                                            crystal                                                                            (isopro-                                                                           6.31(t, J=6.8Hz, 1H), 6.83(d,                                                                1690, 1606,                                                                              C  H  N                                        panol)                                                                             J=8.5Hz, 1H), 7.98-7.10(m,                                                                   1504, 1485,                                                                          Found                                                                             71.89                                                                            4.44                                                                             7.18                                          2H), 7.44-7.58(m, 3H), 7.58-                                                                 1248   Calcd.                                                                            71.99                                                                            4.28                                                                             7.00                                          7.70(m, 2H), 7.73(dd, J=2.2 &                                                 8.5Hz, 1H), 7.95(d, J=2.2Hz,                                                  1H), 8.20(s, 1H)                                               67   white                                                                              290-291                                                                            (DMSO-d.sub.6) 4.7-5.7(m, 4H),                                                               (KBr tablet)                                                                         C.sub.25 H.sub.17 F.sub.3 N.sub.2                                             O.sub.3 .0.5C.sub.3 H.sub.8 O            (E-51b')                                                                           crystal                                                                            (dec.)                                                                             6.33(t, J=6.7Hz, 1H), 6.83(d,                                                                1695, 1606,                                                                              C  H  N                                        (isopro-                                                                           J=8.5Hz, 1H), 7.43-7.62(m,                                                                   1501, 1325,                                                                          Found                                                                             66.49                                                                            4.55                                                                             5.74                                     panol)                                                                             6H), 7.72(dd, J=2.2 & 8.5Hz,                                                                 1242, 1123,                                                                          Calcd.                                                                            66.25                                                                            4.41                                                                             5.83                                          1H), 7.95(d, J=2.2Hz, 1H),                                                                    998                                                           8.00(s, 1H), 8.41(s, 1H)                                       68   white                                                                              286-288                                                                            (DMSO-d.sub.6) 4.7-5.6(m, 4H),                                                               (KBr tablet)                                                                         C.sub.25 H.sub.17 F.sub.3 N.sub.2                                             O.sub.3                                  (E-52b)                                                                            crystal                                                                            (dec.)                                                                             6.34(t, J=7.0Hz, 1H), 6.83(d,                                                                1695, 1605,                                                                              C  H  N                                        (isopro-                                                                           J=8.5Hz, 1H), 7.47-7.63(m,                                                                   1345, 1304,                                                                          Found                                                                             66.85                                                                            3.83                                                                             6.15                                     panol)                                                                             6H), 7.73(dd, J=2.2 & 8.5Hz,                                                                 1248, 1117,                                                                          Calcd.                                                                            66.67                                                                            3.80                                                                             6.22                                          1H), 7.83(d, J=8.3Hz, 1H),                                                                   1000                                                           7.96(d, J=2.2Hz, 1H), 8.46(s,                                                 1H)                                                            69   white                                                                              277-278                                                                            (DMSO-d.sub.6) 4.7-5.6(m, 4H),                                                               (KBr tablet)                                                                         C.sub.24 H.sub.17 ClN.sub.2                                                   O.sub.3.0.5H.sub.2 O                     (E-53b')                                                                           crystal                                                                            (isopro-                                                                           6.30(t, J=6.7Hz, 1H), 6.83(d,                                                                1690, 1606,                                                                              C  H  N                                        panol)                                                                             J=8.5Hz, 1H), 7.2-7.75(m,                                                                    1488, 1245,                                                                          Found                                                                             67.78                                                                            4.01                                                                             6.56                                          7H), 7.72(dd, J=2.2 & 8.6Hz,                                                                 1194, 1004                                                                           Calcd.                                                                            67.69                                                                            4.26                                                                             6.58                                          1H), 7.94(d, J=2.2Hz, 1H),                                                    8.27(s, 1H)                                                    70   pale 310-311.5                                                                          (DMSO-d.sub.6) 4.7-5.6(m, 4H),                                                               (KBr tablet)                                                                         C.sub.24 H.sub.17 ClN.sub.2 O.sub.3.0                                         .25H.sub.2 O                             (E-54b')                                                                           yellow                                                                             (isopro-                                                                           6.30(t, J=6.7Hz, 1H), 6.83(d,                                                                1695, 1605,                                                                              C  H  N                                   crystal                                                                            panol)                                                                             J=8.6Hz, 1H), 7.15-7.65(m,                                                                   1488, 1242,                                                                          Found                                                                             68.48                                                                            4.12                                                                             6.61                                          7H), 7.73(dd, J=2.2 & 8.5Hz,                                                                 1102, 1001                                                                           Calcd.                                                                            68.40                                                                            4.19                                                                             6.65                                          1H), 7.95(d, J=2.2Hz, 1H),                                                    8.24(s, 1H)                                                    71   white                                                                              290-293                                                                            (DMSO-d.sub.6) 4.85-5.6(m, 4H),                                                              (KBr tablet)                                                                         C.sub.24 H.sub.17 N.sub.3 O.sub.5.0.2                                         H.sub.2 O                                (E-55b')                                                                           crystal                                                                            (isopro-                                                                           6.35(t, J=6.7Hz, 1H), 6.83(d,                                                                1677, 1607,                                                                              C  H  N                                        panol-                                                                             J=8.6Hz, 1H), 7.46-7.74(m,                                                                   1517, 1346,                                                                          Found                                                                             66.85                                                                            3.88                                                                             9.61                                     water)                                                                             6H), 7.95(d, J=2.2Hz, 1H),                                                                   1319, 1286,                                                                          Calcd.                                                                            66.88                                                                            4.07                                                                             9.75                                          8.15(dd, J=2.2, 9.0Hz, 1H),                                                                  1247, 1004                                                     8.50-8.53(m, 2H)                                               72   white                                                                              287-290                                                                            (DMSO-d.sub.6) 4.8-5.6(m, 4H),                                                               (KBr tablet)                                                                         C.sub.24 H.sub.17 N.sub.3 O.sub.5        (E-56b)                                                                            crystal                                                                            (isopro-                                                                           6.34(t, J=6.8Hz, 1H), 6.83                                                                   1690, 1604,                                                                              C  H  N                                        panol)                                                                             (d, J=8.5Hz, 1H), 7.48-8.10                                                                  1520, 1486,                                                                          Found                                                                             66.17                                                                            3.89                                                                             9.95                                          (m, 9H), 8.58(s, 1H)                                                                         1343, 1240,                                                                          Calcd.                                                                            67.44                                                                            4.01                                                                             9.83                                                         1201                                            73   white                                                                              257-258                                                                            (DMSO-d.sub.6) 3.77(s, 3H), 4.8-                                                             (KBr tablet)                                                                         C.sub.25 H.sub.20 N.sub.2 O.sub.4.0.2                                         H.sub.2 O                                (E-61b)                                                                            crystal                                                                            (meth-                                                                             5.6(m, 4H), 6.27(t, J=6.8Hz,                                                                 3450, 1715,                                                                              C  H  N                                        anol)                                                                              1H), 6.82(d, J=8.5Hz, 1H),                                                                   1602, 1488,                                                                          Found                                                                             72.35                                                                            4.78                                                                             6.73                                          6.82-7.62(m, 6H), 7.16(bs,                                                                   1243,  837,                                                                          Calcd.                                                                            72.17                                                                            4.94                                                                             6.73                                          1H), 7.72(dd, J=2.2, 8.5Hz,                                                                   770                                                           1H), 7.93(d, J=2.2Hz, 1H),                                                    8.11(bs, 1H)                                                   74   white                                                                              272-273                                                                            (DMSO-d.sub.6) 3.73(s, 3H), 6.30                                                             (KBr tablet)                                                                         C.sub.25 H.sub.20 N.sub.2 O.sub.4.0.3                                         H.sub.2 O                                (E-62b)                                                                            crystal                                                                            (meth-                                                                             (t, J=7.0Hz, 1H), 6.71(d, J=                                                                 3450, 1680,                                                                              C  H  N                                        anol)                                                                              2.2Hz, 1H), 6.82(dd, J=2.2,                                                                  1605, 1505,                                                                          Found                                                                             70.86                                                                            4.69                                                                             6.67                                          8.5Hz, 1H), 6.83(d, J=8.5Hz,                                                                 1245, 1002,                                                                          Calcd.                                                                            70.74                                                                            5.07                                                                             6.60                                          1H), 7.46-7.62(m, 5H), 7.72                                                                   815,  772                                                     (dd, J=2.2, 8.5Hz, 1H), 7.96                                                  (d, J=2.2Hz, 1H), 8.10(bs, 1H)                                 75   white                                                                              182-184                                                                            (DMSO-d.sub.6) 4.6-5.6(m, 4H),                                                               (KBr tablet)                                                                         C.sub.31 H.sub.24 N.sub.2 O.sub.4.H.s                                         ub.2 O                                   (E-81b')                                                                           crystal                                                                            (aceto-                                                                            5.79(s, 1H), 6.25(t, J=6.7Hz,                                                                1690, 1605,                                                                              C  H  N                                        nitrile)                                                                           1H), 6.82(d, J=8.5Hz, 1H),                                                                   1491, 1245,                                                                          Found                                                                             73.74                                                                            5.01                                                                             5.35                                          7.1-7.65(m, 12H), 7.71(dd,                                                                   1004   Calcd.                                                                            73.50                                                                            5.17                                                                             5.53                                          J=2.1 & 8.5Hz, 1H), 7.92(d,                                                   J=2.1Hz, 1H), 8.17(s, 1H)                                      76   white                                                                              270-271                                                                            (DMSO-d.sub.6) 4.65-5.80(m, 4H),                                                             (KBr tablet)                                                                         C.sub.31 H.sub.24 N.sub.2 O.sub.4.1.5                                         H.sub.2 O                                (E-82b')                                                                           crystal                                                                            (dec.)                                                                             6.23(t, J=6.7Hz, 1H), 6.85                                                                   1690, 1605,                                                                              C  H  N                                        (aceto-                                                                            (d, J=8.5Hz, 1H), 7.10-7.70                                                                  1487, 1451,                                                                          Found                                                                             72.02                                                                            5.05                                                                             5.11                                     nitrile)                                                                           (m, 12H), 7.73(dd, J=2.1 &                                                                   1242, 1000                                                                           Calcd.                                                                            72.22                                                                            5.28                                                                             5.43                                          8.5Hz, 1H), 7.94(d, J=2.1Hz,                                                  1H), 8.20(s, 1H)                                               77   white                                                                              318-319                                                                            (DMSO-d.sub.6) 4.7-5.7(m, 4H),                                                               (KBr tablet)                                                                         C.sub.25 H.sub.18 N.sub.2 O.sub.5.0.2                                         5H.sub.2 O                               (E-83b')                                                                           crystal                                                                            (dec.)                                                                             6.32(t, J=6.7Hz, 1H), 6.83(d,                                                                1683, 1608,                                                                              C  H  N                                        (isopro-                                                                           J=8.6Hz, 1H), 7.28(d, J=8.3                                                                  1316, 1269,                                                                          Found                                                                             69.45                                                                            4.33                                                                             6.32                                     panol)                                                                             Hz, 1H), 7.4-7.65(m, 4H),                                                                    1249, 1003                                                                           Calcd.                                                                            69.68                                                                            4.33                                                                             6.50                                          7.72(dd, J=2.2 & 8.6Hz, 1H),                                                  7.85(d, J=8.3Hz, 1H), 7.95(d,                                                 J=2.2Hz, 1H), 8.23(s, 1H),                                                    8.34(s, 1H)                                                    78   white                                                                              321-323                                                                            (DMSO-d.sub.6) 4.7-5.7(m, 4H),                                                               (KBr tablet)                                                                         C.sub.25 H.sub.18 N.sub.2 O.sub.5        (E-84b)                                                                            crystal                                                                            (dec.)                                                                             6.28(t, J=6.8Hz, 1H), 6.83(d,                                                                1686, 1608,                                                                              C  H  N                                        (ethanol)                                                                          J=8.5Hz, 1H), 7.4-7.85(m,                                                                    1311, 1265,                                                                          Found                                                                             70.54                                                                            4.27                                                                             6.28                                          8H), 7.95(d, J=2.2Hz, 1H),                                                                   1243, 1122,                                                                          Calcd.                                                                            70.42                                                                            4.25                                                                             6.57                                          8.41(s, 1H)    1006                                            79   white                                                                              275-277                                                                            (DMSO-d.sub.6) 2.25(s, 3H), 2.28                                                             (KBr tablet)                                                                         C.sub.26 H.sub.22 N.sub.2 O.sub.3.0.2                                         5H.sub.2 O                               (E-89b')                                                                           crystal                                                                            (isopro-                                                                           (s, 3H), 2.48-2.51(m, 2H),                                                                   1683, 1606,                                                                              C  H  N                                        panol-                                                                             4.8-5.4(m, 4H), 6.24(t, J=                                                                   1488, 1244,                                                                          Found                                                                             75.23                                                                            5.29                                                                             6.73                                     water)                                                                             7.0Hz, 1H) 6.80(s, 1H), 6.82                                                                 1002   Calcd.                                                                            75.25                                                                            5.46                                                                             6.75                                          (d, J=8.5Hz, 1H), 7.38(s, 1H),                                                7.45-7.65(m, 4H), 7.71(dd,                                                    J=2.2, 8.5Hz, 1H), 7.93(d,                                                    J=2.2Hz, 1H), 8.02(s, 1H)                                      80   white                                                                              235-237                                                                              --             --   C.sub.26 H.sub.22 N.sub.2 O.sub.3.C.s                                         ub.3 H.sub.8 O.HCl                       (E-89b")                                                                           crystal                                                                            (isopro-                       C  H  N                                        panol)                     Found                                                                             68.41                                                                            5.98                                                                             5.73                                                                Calcd.                                                                            68.42                                                                            6.14                                                                             5.50                           81   white                                                                              241-242                                                                              --             --   C.sub.26 H.sub.21 N.sub.2 O.sub.3                                             Na.1.5H.sub.2 O                          (E-89b'")                                                                          crystal                                                                            (water)                        C  H  N                                                                   Found                                                                             68.19                                                                            5.04                                                                             5.87                                                                Calcd.                                                                            67.96                                                                            5.27                                                                             6.10                           82   white                                                                              281.5-283                                                                          (DMSO-d.sub.6) 2.29 & 2.31(each s,                                                           (KBr tablet)                                                                         C.sub.26 H.sub.22 N.sub.2 O.sub.3.0.5                                         H.sub.2 O                                (Z-89b)                                                                            crystal                                                                            (dec.)                                                                             6H), 5.1-5.5(m, 4H), 5.81(t,                                                                 1680, 1608,                                                                              C  H  N                                        (isopro-                                                                           J=6.6Hz, 1H), 7.02(d, J=9.3                                                                  1495, 1303,                                                                          Found                                                                             74.82                                                                            5.51                                                                             6.50                                     panol)                                                                             Hz, 1H), 7.22(bs, 1H), 7.30-                                                                 1244, 1106,                                                                          Calcd.                                                                            74.45                                                                            5.53                                                                             6.68                                          7.45(m, 5H), 7.82-7.86(m,                                                                     999                                                           2H), 8.18(bs, 1H)                                              83   white                                                                              277.5-278                                                                          (DMSO-d.sub.6) 2.24 & 2.27 (each                                                             (KBr tablet)                                                                         C.sub.27 H.sub.24 N.sub.2 O.sub.3        (E-90b)                                                                            solid                                                                              (isopro-                                                                           s, 6H), 3.48(s, 2H), 4.6-5.5                                                                 1708, 1489,                                                                              C  H  N                                        panol)*                                                                            (m, 4H), 6.14(t, J=7.0Hz, 1H),                                                               1224, 1010                                                                           Found                                                                             76.16                                                                            5.92                                                                             5.68                                          6.69(d, J=8.5Hz, 1H), 6.78(s,                                                                       Calcd.                                                                            76.39                                                                            5.70                                                                             6.60                                          1H), 7.06(dd, J=2.2 & 8.6Hz,                                                  1H), 7.22(s, 1H), 7.40(s,                                                     1H), 7.41-7.65(m, 4H), 8.08                                                   (s, 1H)                                                        84   white                                                                               267-268                                                                           (DMSO-d.sub.6) 2.25 & 2.28 (each                                                             (KBr tablet)                                                                         C.sub.26 H.sub.22 N.sub.2 O.sub.3.0.5                                         C.sub.3 H.sub.8 O                        (E-93b')                                                                           crystal                                                                            (dec.)                                                                             s, 6H), 4.6-5.6(m, 4H), 6.28                                                                 1692, 1411,                                                                              C  H  N                                        (ethanol-                                                                          (t, J=7.0Hz, 1H), 6.81(s, 1H),                                                               1312, 1025                                                                           Found                                                                             74.84                                                                            5.77                                                                             6.08                                     isopro-                                                                            7.26(s, 1H), 7.40-7.67(m,                                                                           Calcd.                                                                            74.98                                                                            5.95                                                                             6.36                                     panol)                                                                             7H), 8.08(s, 1H)                                               85   white                                                                              290.5-292                                                                          (DMSO-d.sub.6) 4.8-5.4(m, 4H),                                                               (KBr tablet)                                                                         C.sub.26 H.sub.22 N.sub.2 O.sub.3.0.2                                         5H.sub.2 O                               (E-94b')                                                                           crystal                                                                            (dec.)                                                                             6.23(d, J=6.9Hz, 1H), 6.75-                                                                  1683, 1480,                                                                              C  H  N                                        (dioxane)                                                                          7.25(m, 4H), 7.34(dd, J=1.6 &                                                                1285, 1268,                                                                          Found                                                                             75.56                                                                            5.31                                                                             6.63                                          7.8Hz, 1H), 7.40(bs, 1H),                                                                    1217, 1007                                                                           Calcd.                                                                            75.25                                                                            5.47                                                                             6.75                                          7.74(d, J=7.8Hz, 1H), 7.93(s,                                                 1H), 8.01-8.06(m, 2H)                                          86   white                                                                              302-306                                                                            (DMSO-d.sub.6) 2.32(s, 3H), 2.45                                                             (KBr tablet)                                                                          C.sub.26 H.sub.22 N.sub.2 O.sub.3       (E-96b)                                                                            crystal                                                                            (toluene)                                                                          (s, 3H), 4.80-5.30(b, 2H),                                                                   3420, 1673,                                                                              C  H  N                                             6.27(t, J=6.8Hz, 1H), 6.83(d,                                                                1605, 1503,                                                                          Found                                                                             75.87                                                                            5.24                                                                             6.43                                          J=8.6Hz, 1H), 6.92 & 7.05                                                                    1227, 1001                                                                           Calcd.                                                                            76.08                                                                            5.40                                                                             6.82                                          (ABq, J=8.2Hz, 2H), 7.46-7.63                                                 (m, 6H), 7.23(dd, J=2.2 & 8.6                                                 Hz, 1H), 7.93(d, J=2.2Hz, 1H),                                                8.31(s, 1H)                                                    87   white                                                                              308-311                                                                            (Pyridine-d.sub.5) 2.37(s, 3H),                                                              (KBr tablet)                                                                         C.sub.26 H.sub.22 N.sub.2 O.sub.3.0.3                                         C.sub.3 H.sub.8 O                        (E-99b')                                                                           crystal                                                                            (isopro-                                                                           2.77(s, 3H), 4.80-4.93(b,                                                                    3420, 1673,                                                                              C  H  C                                        panol-                                                                             2H), 4.85-5.69(m, 2H), 6.26                                                                  1605, 1504,                                                                          Found                                                                             75.36                                                                            5.42                                                                             6.18                                     meth-                                                                              (t, J=7.1Hz, 1H), 6.70(s, 1H),                                                               1309, 1227,                                                                          Calcd.                                                                            75.40                                                                            5.70                                                                             6.52                                     anol-                                                                              6.98(s, 1H), 7.10(d, J=8.9Hz,                                                                1200, 1001                                                water)                                                                             1H), 7.20-7.56(m, 4H), 8.15                                                   (s, 1H), 8.25(dd, J= 2.2 & 8.6                                                Hz, 1H), 8.45(d, J=2.0Hz, 1H)                                  88   white                                                                              273  (DMSO-d.sub.6) 4.6-5.6(m, 4H),                                                               (KBr tablet)                                                                         C.sub.25 H.sub.18 N.sub.2 O.sub.5.0.5                                         H.sub.2 O                                (E-100b')                                                                          crystal                                                                            (dec.)                                                                             5.99(s, 2H), 6.26(t, J=6.7Hz,                                                                1689, 1606,                                                                              C  H  C                                        (isopro-                                                                           1H), 6.78(s, 1H), 6.84(d, J=                                                                 1486, 1350,                                                                          Found                                                                             68.83                                                                            4.69                                                                             6.12                                     panol)                                                                             8.5Hz, 1H), 7.13(s, 1H), 7.4-                                                                1244, 1001                                                                           Calcd.                                                                            68.95                                                                            4.40                                                                             6.43                                          7.65(m, 4H), 7.73(dd, J=2.2 &                                                 8.5Hz, 1H), 7.93(d, J=2.2Hz,                                                  1H), 7.99(s, 1H)                                               89   white                                                                              290-292                                                                            (DMSO-d.sub.6) 3.72(s, 3H), 3.77                                                             (KBr tablet)                                                                         C.sub.26 H.sub.22 N.sub.2 O.sub.5        (E-101b)                                                                           crystal                                                                            (partially                                                                         (s, 3H), 4.70-5.7(m, 4H),                                                                    2942, 2838,                                                                              C  H  C                                        dec.)                                                                              6.31(t, J=6.8Hz, 1H), 6.74(s,                                                                1697, 1606,                                                                          Found                                                                             70.25                                                                            5.03                                                                             6.36                                     (isopro-                                                                           1H), 6.84(d, J=8.5Hz, 1H),                                                                   1492, 1229,                                                                          Calcd.                                                                            70.58                                                                            5.01                                                                             6.33                                     panol)                                                                             7.19(s, 1H), 7.45- 7.64(m,                                                                   1001                                                           4H), 7.73(dd, J=2.0 & 8.5Hz,                                                  1H), 7.95(d, J=2.0Hz, 1H),                                                    8.04(s, 1H)                                                    90   white                                                                              259-261                                                                            (DMSO-d.sub.6) 3.69 & 3.89 (each                                                             (KBr tablet)                                                                         C.sub.26 H.sub.22 N.sub.2 O.sub.5.0.2                                         5H.sub.2 O                               (E-106b')                                                                          solid                                                                              (dec.)                                                                             s, 6H), 4.5-5.8(m, 4H), 6.24-                                                                1606, 1505,                                                                              C  H  N                                        (aceto-                                                                            6.32(m, 3H), 6.83(d, J=8.5                                                                   1248, 1205,                                                                          Found                                                                             70.06                                                                            4.89                                                                             6.26                                     nitrile)*                                                                          Hz, 1H), 7.43-7.60(m, 3H),                                                                   1150, 1006                                                                           Calcd.                                                                            69.87                                                                            5.07                                                                             6.27                                          7.61(d, J=5.4Hz, 1H), 7.72                                                    (dd, J=2.0 & 8.5Hz, 1H), 7.94                                                 (s, 2H)                                                        91   white                                                                              278-279                                                                            (DMSO-d.sub.6) 3.61 & 3.75 (each                                                             (KBr tablet)                                                                         C.sub.26 H.sub.22 N.sub.2 O.sub.5        (E-107b)                                                                           solid                                                                              (dec.)                                                                             s, 6H), 4.9-5.7(m, 4H), 6.18                                                                 1700, 1608,                                                                              C  H  N                                        (aceto-                                                                            (t, J=6.5Hz, 1H), 6.37(bs,                                                                   1500, 1307,                                                                          Found                                                                             69.60                                                                            4.90                                                                             6.12                                     nitrile)*                                                                          1H), 6.73(bs, 1H), 6.81(d, J=                                                                1255, 1122,                                                                          Calcd.                                                                            69.87                                                                            5.07                                                                             6.27                                          8.6Hz, 1H), 7.37-7.63(m, 4H),                                                                1003                                                           7.70(dd, J=2.2 & 8.6Hz, 1H),                                                  7.92(d, J=2.2Hz, 1H), 8.06                                                    (bs, 1H)                                                       92   white                                                                              287-289                                                                            (DMSO-d.sub.6) 4.7-5.6(m, 4H),                                                               (KBr tablet)                                                                         C.sub.24 H.sub.16 Cl.sub.2 N.sub.2                                            O.sub.3.0.5C.sub.2 H.sub.3 N             (E-108b')                                                                          crystal                                                                            (aceto-                                                                            6.83(d, J=8.5Hz, 1H), 7.44                                                                   1698, 1607,                                                                          .0.25H.sub.2 O                                     nitrile-                                                                           (s, 1H), 7.46-7.63(m, 4H),                                                                   1488, 1312,                                                                              C  H  N                                        isopro-                                                                            7.73(dd, J=2.2, 8.5Hz, 1H),                                                                  1262,  996,                                                                          Found                                                                             63.10                                                                            3.56                                                                             7.19                                     panol)                                                                             7.89(s, 1H), 7.95(d, J=2.2Hz,                                                                 765   Calcd.                                                                            63.04                                                                            3.81                                                                             7.35                                          1H), 8.31(s, 1H)                                               93   white                                                                              287-290                                                                            (DMSO-d.sub.6) 4.8-5.6(m, 4H),                                                               (KBr tablet)                                                                         C.sub.28 H.sub.20 N.sub.2 O.sub.3.0.5                                         C.sub.3 H.sub.7 NO.                      (E-109b')                                                                          crystal                                                                            (dec.)                                                                             6.37(t, J=8.5Hz, 1H), 6.83(d,                                                                1676, 1602,                                                                          0.25H.sub.2 O                                      N,N- J= 8.6Hz, 1H), 7.37-8.03(m,                                                                  1514, 1382,                                                                              C  H  N                                        dimethyl-                                                                          11H), 8.21(s, 1H), 8.46(s,                                                                   1244, 1194,                                                                          Found                                                                             74.83                                                                            5.02                                                                             7.74                                     forma-                                                                             1H), 12.7(bs, 1H)                                                                            1005   Calcd.                                                                            74.82                                                                            5.11                                                                             7.39                                     mide)                                                               94   white                                                                              260-263                                                                            (DMSO-d.sub.6) 4.8-5.4(m, 4H),                                                               (KBr tablet)                                                                         C.sub.23 H.sub.17 N.sub.3 O.sub.3        (E-110b)                                                                           crystal                                                                            (dec.)                                                                             6.31(t, J=5.2Hz, 1H), 6.83(d,                                                                1683, 1605,                                                                              C  H  N                                        (isopro-                                                                           J=8.5Hz, 1H), 7.27(dd, J=                                                                    1505, 1412,                                                                          Found                                                                             71.92                                                                            4.31                                                                             10.94                                    panol)                                                                             4.8 & 8.1Hz, 1H), 7.44-7.58(m,                                                               1393, 1313,                                                                          Calcd.                                                                            72.05                                                                            4.47                                                                             10.96                                         4H), 7.71(dd, J=2.2 & 8.5Hz,                                                                 1247, 1206,                                                    1H), 7.90(d, J=2.2Hz, 1H),                                                                   1000,  772                                                     8.06(d, J=7.2Hz, 1H), 8.33                                                    (dd, J=1.2 & 4.8Hz, 1H), 8.49                                                 (bs, 1H)                                                       95   white                                                                              234-236                                                                            (DMSO-d.sub.6) 2.67(s, 3H), 4.5-                                                             (KBr tablet)                                                                         C.sub.26 H.sub.22 N.sub.2 O.sub.3                                             S.0.25H.sub.2 O                          (E-113b')                                                                           crystal                                                                           (dec.)                                                                             5.7(m, 4H), 6.06(t, J=6.6                                                                    2928, 1685,                                                                              C  H  N                                        (isopro-                                                                           Hz, 1H), 6.84(d, J=8.5Hz, 1H),                                                               1608, 1488,                                                                          Found                                                                             69.33                                                                            4.57                                                                             6.39                                     panol)                                                                             7.13-7.65(m, 8H), 7.72(dd, J=                                                                1450, 1314,                                                                          Calcd.                                                                            69.35                                                                            4.71                                                                             6.47                                          2.2 & 8.5Hz, 1H), 7.93(d, J=                                                                 1232, 1008,                                                    2.2Hz, 1H)      774,  742                                      96   white                                                                              318  (DMSO-d.sub.6) 2.39(s, 3H), 4.6-                                                             (KBr tablet)                                                                         C.sub.25 H.sub.20 N.sub.2 O.sub.3        (E-114b)                                                                           crystal                                                                            (dec.)                                                                             5.6(m, 4H), 6.17(t, J=6.7                                                                    1695, 1606,                                                                              C  H  N                                        (isopro-                                                                           Hz, 1H), 6.83(d, J=8.5Hz, 1H),                                                               1487, 1404,                                                                          Found                                                                             75.76                                                                            5.05                                                                             7.00                                     panol)                                                                             7.12-7.16(m, 3H), 7.50-7.66                                                                  1310, 1240,                                                                          Calcd.                                                                            75.74                                                                            5.09                                                                             7.06                                          (m, 5H), 7.72(dd, J=2.1 & 8.5                                                                1001                                                           Hz, 1H), 7.96(d, J=2.1Hz, 1H)                                  97   white                                                                              215-219                                                                            (DMSO-d.sub.6) 5.0-5.7(m, 4H),                                                               (KBr tablet)                                                                         C.sub.23 H.sub.17 N.sub.3 O.sub.3        (E-118b)                                                                           crystal                                                                             (isopro-                                                                          6.40(t, J=7.0Hz, 1H), 6.85(d,                                                                1686, 1604,                                                                              C  H  N                                        panol-                                                                             J=8.5Hz, 1H), 7.38-7.76(m,                                                                   1407, 1306,                                                                          Found                                                                             72.19                                                                            4.45                                                                             11.20                                    water)                                                                             8H), 7.93(d, J=2.0Hz, 1H),                                                                   1261, 1248,                                                                          Calcd.                                                                            72.05                                                                            4.47                                                                             10.96                                         8.05(d, J=8.5Hz, 1H), 12.76                                                                   996,  747                                                     (bs, 1H)                                                       98   white                                                                              201-203                                                                            (DMSO-d.sub.6) 5.05-5.65(m, 4H),                                                             (KBr tablet)                                                                         C.sub.24 H.sub.18 N.sub.2 O.sub.3.1.4                                         H.sub.2 O                                (E-121b')                                                                          crystal                                                                            (isopro-                                                                           6.30(t, J=6.3Hz, 1H), 6.62(d,                                                                1608, 1481,                                                                              C  H  N                                        panol)*                                                                            J=2.2Hz, 1H), 6.81(d, J=8.6                                                                  1373, 1313,                                                                          Found                                                                             70.63                                                                            4.87                                                                             6.85                                          Hz, 1H), 7.1-7.75(m, 7H),                                                                    1285, 1101,                                                                          Calcd.                                                                            70.72                                                                            5.14                                                                             6.87                                          7.95(d, J=2.2Hz, 1H), 8.09(d,                                                                1009                                                           J=5.9Hz, 1H), 8.24(d, J=6.6                                                   Hz, 1H)                                                        99   white                                                                              291-295                                                                            (Pyridine-d.sub.5) 2.36(s, 1.5H),                                                            (KBr tablet)                                                                         C.sub.25 H.sub.20 N.sub.2 O.sub.3        (mixture                                                                           crystal                                                                            (toluene)                                                                           2.40(s, 1.5H), 4.85-5.10(m,                                                                 3450, 1683,                                                                              C  H  N                              of E-47b       2H), 4.80-5.64(m, 2H), 6.26                                                                  1608, 1505,                                                                          Found                                                                             74.90                                                                            4.92                                                                             6.84                           and            (t, J=7.2Hz, 1H), 6.85(s, 1H),                                                               1243, 1007,                                                                          Calcd.                                                                            74.74                                                                            5.08                                                                             7.07                           E-48b)         7.00(d, J=8.6Hz, 1H), 7.12-                                                                   775                                                           7.58(m, 6H), 8.22(s, 1H),                                                     8.24(dd, J=2.2 & 8.6Hz, 1H),                                                  8.44(d, J=2.2Hz, 1H)                                           100  white                                                                              226-228                                                                            (DMSO-d.sub.6) 0.8-1.6(m, 11H),                                                              (KBr tablet)                                                                         C.sub.31 H.sub.31 N.sub.3 O.sub.4.0.6                                         C.sub.3 H.sub.8 O                        (mixture                                                                           solid                                                                              (isopro-                                                                           3.2-3.3(m, 2H), 4.80-5.65(m,                                                                 1694, 1611,                                                                              C  H  N                              of E-85b' panol)                                                                             4H), 6.31(t, J=7.8Hz, 1H),                                                                   1223, 1130                                                                           Found                                                                             72.40                                                                            6.73                                                                             7.38                           and            6.83(d, J=8.5Hz, 1H), 7.2-7.8                                                                1004   Calcd.                                                                            72.33                                                                            6.44                                                                             7.71                           E-86b')        (m, 7H), 7.94(d, J=2.2Hz, 1H),                                                8.19-8.38(m, 3H)                                               101  white                                                                              251-255                                                                            (DMSO-d.sub.6) 4.51(t, J=6.6Hz,                                                              (KBr tablet)                                                                         C.sub. 32 H.sub.25 N.sub.3 O.sub.4       (mixture                                                                           solid                                                                              (isopro-                                                                           2H), 4.7-5.7(m, 4H), 6.26-                                                                   1670, 1631,                                                                              C  H  N                              of E-87b  panol)                                                                             6.35(m, 1H), 6.84(d, J=8.8Hz,                                                                1317, 1246,                                                                          Found                                                                             74.62                                                                            4.61                                                                             7.85                           and            1H), 7.22-8.36(m, 14H), 7.95                                                                 1205, 1006                                                                           Calcd.                                                                            74.55                                                                            4.89                                                                             8.15                           E-88b)         (d, J=2.2Hz, 1H), 8.98-9.05                                                   (m, 1H)                                                        102  white                                                                              303-308                                                                            (DMSO-d.sub.6) 2.70-3.42(m, 4H),                                                             (KBr tablet)                                                                         C.sub.25 H.sub.20 N.sub.2 O.sub.2        (Z-172b)                                                                           crystal                                                                            (isopro-                                                                           5.00-5.30(m, 2H), 6.04(t, J=                                                                 1716, 1670,                                                                              C  H  N                                        panol)                                                                             7.0Hz, 1H), 7.03-7.43(m, 9H),                                                                1493, 1288,                                                                          Found                                                                             78.91                                                                            5.21                                                                             7.40                                          8.00-8.08(m, 1H), 8.31(s,                                                                    1103   Calcd.                                                                            78.93                                                                            5.30                                                                             7.36                                          2H), 8.36(dd, J=1.3 & 7.9Hz,                                                  1H)                                                            103  white                                                                              262-266                                                                            (Pyridine-d.sub.5) 2.28(s, 6H),                                                              (KBr tablet)                                                                         C.sub.27 H.sub.24 N.sub.2 O.sub.2        (Z-173b)                                                                           crystal                                                                            (isopro-                                                                           2.65-2.87(m, 2H), 3.02-3.34                                                                  3430, 1678,                                                                              C  H  N                                        panol)                                                                             (m, 2H), 4.55-4.86(m, 2H),                                                                   1454, 1256,                                                                          Found                                                                             79.21                                                                            5.86                                                                             6.91                                          6.02(t, J=4.2Hz, 1H), 6.87-                                                                  1210   Calcd.                                                                            79.39                                                                            5.92                                                                             6.86                                          7.78(m, 7H), 8.14(s, 1H),                                                     8.43(dd, J=1.7 & 8.0Hz, 1H),                                                  8.61(d, J=1.1Hz, 1H)                                           103  white                                                                              288-289                                                                            (Pyridine-d.sub.5) 2.30(s, 3H),                                                              (KBr tablet)                                                                         C.sub.27 H.sub.24 N.sub.2 O.sub.2        (Z-173b)                                                                           crystal                                                                            (isopro-                                                                           2.33(s, 3H), 2.73-3.00(m,                                                                    3430, 1678,                                                                              C  H  N                                        panol)                                                                             2H), 3.12-3.44(m, 2H), 4.80-                                                                 1454, 1256,                                                                          Found                                                                             79.40                                                                            5.89                                                                             6.88                                          5.20(m, 2H), 6.04(t, J=4.2Hz,                                                                1210   Calcd.                                                                            79.39                                                                            5.92                                                                             6.86                                          1H), 7.05-7.58(m, 7H), 8.20                                                   (s, 1H), 8.33(d, J=1.7Hz, 1H),                                                8.38(dd, J=1.7 & 8.6Hz, 1H)                                    104  white                                                                              263-265                                                                            (Pyridine-d.sub.5) 4.70-5.00(m,                                                              (KBr tablet)                                                                         C.sub.25 H.sub.18 N.sub.2 O.sub.2        (177b)                                                                             crystal                                                                            (isopro-                                                                           2H), 5.50-5.83(m, 1H), 6.90-                                                                 3420, 1695,                                                                              C  H  N                                        panol)                                                                             7.00(m, 2H), 7.05-7.48(m,                                                                    1494, 1250,                                                                          Found                                                                             79.10                                                                            4.58                                                                             7.66                                          7H), 7.53-7.79(m, 2H), 8.01                                                                  1183   Calcd.                                                                            79.35                                                                            4.79                                                                             7.40                                          (s, 1H)                                                        105  white                                                                              306-308                                                                            (Pyridine-d.sub.5) 2.26(s, 3H),                                                              (KBr tablet)                                                                         C.sub.27 H.sub.22 N.sub.2 O.sub.2.0.3                                         C.sub.3 H.sub.8 O                        (E-178b')                                                                          crystal                                                                            (isopro-                                                                           2.31(s, 3H), 4.70(dd, J=9.6 &                                                                3450, 1678,                                                                              C  H  N                                        panol)                                                                             15.6Hz, 1H), 4.95(dd, J=4.2 &                                                                1504, 1454,                                                                          Found                                                                             78.89                                                                            5.51                                                                             5.99                                          15.6Hz, 1H), 5.71(dd, J=4.2 &                                                                1280, 1210,                                                                          Calcd.                                                                            78.94                                                                            5.79                                                                             6.39                                          9.6Hz, 1H), 6.98-7.56(m, 6H),                                                                 769                                                           7.74(s, 1H), 8.11(s, 1H),                                                     8.35(dd, J=1.7 & 8.0Hz, 1H),                                                  8.45(d, J=1.7Hz, 1H)                                           106  white                                                                              280-283                                                                            (DMSO-d.sub.6) 2.25(s, 6H), 3.60                                                             (KBr tablet)                                                                         C.sub.28 H.sub.24 N.sub.2 O.sub.2.0.2                                         H.sub.2 O                                (E-179b')                                                                           crystal                                                                           (isopro-                                                                           (s, 2H), 4.59(dd, J=9.5 & 15.4                                                               3406, 2924,                                                                              C  H  N                                        panol)                                                                             Hz, 1H), 5.04(dd, J=4.6 & 15.4                                                               1707, 1496,                                                                          Found                                                                             79.42                                                                            5.97                                                                             6.48                                          Hz, 1H), 5.60(dd, J=4.6 & 9.5                                                                1287   Calcd.                                                                            79.56                                                                            5.75                                                                             6.26                                          Hz, 1H), 6.74(s, 1H), 6.93 &                                                  7.04(ABq, J=12.0Hz, 2H), 7.35                                                 (s, 1H), 7.20-7.60(m, 7H),                                                    8.04(s, 1H)                                                    __________________________________________________________________________

EXAMPLE 1075-[2-(5,6-Dimethyl-1-benzimidazolyl)ethyl]-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-3-carboxylicacid·0.1 hydrate (Compound 174b')

5-(2-Hydroxyethyl)-3-(4,4-dimethyl-2-oxazoline-2-yl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten(Compound s), 0.32 g, obtained in Reference Example 19 was dissolved in9.6 ml of methylene chloride, and 3.2 ml of triethylamine and 0.2 ml ofmethanesulfonyl chloride were successively added to the solution. Themixture was stirred for 1.5 hours at room temperature, and extractedwith 100 ml of methylene chloride. The extract was washed with 1 Nhydrochloric acid aqueous solution, saturated sodium bicarbonate aqueoussolution and saturated sodium chloride aqueous solution successively,and dried over anhydrous magnesium sulfate. The solvent was distilledoff under reduced pressure to obtain the correspondingmethanesulfonyloxy compound as a crude product. The crude product wasserved as it is for further reaction.

5,6-Dimethylbenzimidazole, 0.21 g, and 62 mg of sodium hydride (oily:60%) were dissolved in 15 ml of tetrahydrofuran and 2.5 ml ofN,N-dimethylformamide. To the solution was dropwise added the crudemethanesulfonyloxy compound dissolved in 10 ml of tetrahydrofuran, andthe mixture was heated under reflux for 4 hours. The mixture wasextracted with 100 ml of ethyl acetate, and washed successively withsaturated sodium bicarbonate aqueous solution and saturated sodiumchloride aqueous solution. The mixture was dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The resulting residue was subjected to silica gel columnchromatography (eluting solvent; ethyl acetate:triethylamine =10:1) togive 0.47 g of5-[2-(5,6-dimethyl-1-benzimidazolyl)ethyl]-3-(4,4-dimethyl-2-oxazoline-2-yl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptenas play yellow oily.

The above-mentioned compound, 0.36 g was dissolved in a solvent mixtureof 18 ml of dioxane and 18 ml of water, and 0.36 mol of concentratedsulfuric acid was added thereto. The mixture was stirred at 60°-80° C.for 1.5 hours, and water was added thereto. The mixture was washed withether, and adjusted to pH6 with 10 N sodium hydroxide aqueous solution.The precipitated solid was taken of by filtration to give 0.19 g of thedesired product.

EXAMPLE 1085-[2-(5,6-Dimethyl-1-benzimidazolyl)ethyl]-5H-dibenzo[a,d]-cyclohepten-3-carboxylicacid·0.8 isopropanol·monohydrate (Compound 180b')

The product was prepared using Compound v obtained in Reference Example22 in a manner similar to Example 107.

The physicochemical properties of the compounds obtained in Examples 107and 108 are shown in Table 5-5.

                                      TABLE 5-5                                   __________________________________________________________________________    Example   MP °C.                                                       No.       (Solvent                                                            (Com-     for                 IR                                              pound                                                                              Appear-                                                                            recrystal-                                                                         NMR            (Method)                                                                             Elemental analysis                       No.) ance lization)                                                                          (Solvent) δ, ppm                                                                       cm.sup.-1                                                                            %                                        __________________________________________________________________________    107  white                                                                              232-235                                                                            (DMSO-d.sub.6) 2.29(s, 6H), 2.53-                                                            (KBr tablet)                                                                         C.sub.27 H.sub.26 N.sub.2 O.sub.2.0.1                                         H.sub.2 O                                (174b')                                                                            crystal                                                                            (isopro-                                                                           2.73(m, 2H), 2.93-3.40(m,                                                                    3450, 2922,                                                                              C  H  N                                        panol)                                                                             4H), 4.08-4.23(m, 2H), 4.23-                                                                 1692, 1657,                                                                          Found                                                                             78.53                                                                            6.35                                                                             6.91                                          4.37(m, 1H), 7.08(s, 1H),                                                                    1496, 1254,                                                                          Calcd.                                                                            78.65                                                                            6.40                                                                             6.79                                          7.14-7.26(m, 5H), 7.40(s,                                                                    1205                                                           1H), 7.70(dd, J=1.7 & 7.8Hz,                                                  1H), 7.82(d, J=1.5Hz, 1H),                                                    7.99(s, 1H)                                                    108  yellow                                                                             302-306                                                                            (DMSO-d.sub.6) 2.10-2.22(m, 2H),                                                             (KBr tablet)                                                                         C.sub.27 H.sub.24 N.sub.2 O.sub.2.0.4                                         C.sub.3 H.sub.8 O.H.sub.2 O              (180b')                                                                            solid                                                                              (isopro-                                                                           2.28(s, 6H), 3.79-3.84(m,                                                                    3440, 1652 C  H  N                                        panol)*                                                                            2H), 4.30(t, J=7.8Hz, 1H),                                                                   1689, 1652                                                                           Found                                                                             75.31                                                                            6.19                                                                             6.54                                          7.03 & 7.10(ABq, J=12.0Hz,                                                                   1498, 1264                                                                           Calcd.                                                                            75.17                                                                            6.53                                                                             6.21                                          2H), 7.00-7.56(m, 7H), 7.79-                                                  8.06(m, 3H)                                                    __________________________________________________________________________

EXAMPLE 109 Methyl11-(4-pyridyl)thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound8a)

Methyl 11-hydroxy-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compoundb), 4.0 g, obtained in Reference Example 2 was dissolved in 200 ml ofmethylene chloride and 2.5 ml of trifluoroacetic anhydride was added tothe solution. The mixture was stirred at room temperature for an hour.Further 2.5 g of 4-mercaptopyridine and 1 ml of boron trifluoridediethyl ether complex were added to the reaction mixture followed bystirring at room temperature for 2 hours. Then, crushed small ice pieceswere added to the mixture. After stirring for an hour, the solvent wasdistilled off under reduced pressure. The aqueous phase was extractedwith 300 ml of ethyl acetate. The extract was washed successively withsaturated sodium bicarbonate aqueous solution nd saturated sodiumchloride aqueous solution. After drying over anhydrous magnesiumsulfate, the solvent was distilled off under reduced pressure. Theresulting residue was subjected to silica gel column chromatography(eluting solvent; hexane:ethyl acetate: triethylamine=10:10:1) to give2.9 of the product.

EXAMPLE 110 Methyl 11-(4-pyridyl)thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate monofumarate (Compound 8a')

Compound 8a, 1.2 g, obtained in Example 109 was treated in a mannersimilar to Example 10 to give 1.2 g of the objective compound.

EXAMPLE 111 Methyl11-[(3-pyridyl)methyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 14a) EXAMPLE 112 Methyl11-[(3-pyridyl)methyl]thio-6,11-dihydrodibenz[b,e]oxepin-3-carboxylate(Compound 15a) EXAMPLE 113 Methyl11-(benzyl)thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound19a) EXAMPLE 114 Methyl11-(benzyl)thio-6,11-dihydrodibenz[b,e]oxepin-2-acetate (Compound 20a)EXAMPLE 115 Methyl11-(benzothiazolyl)thio-6,11-dihydrodibenz[b,e]oxepin-2-acetate(Compound 126a) EXAMPLE 116 Methyl11-[2-(2-benzimidazolyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 129a) EXAMPLE 117 Methyl11-[2-(1-methyl-2-benzimidazolyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 130a) EXAMPLE 118 Methyl11-[2-[1-(4-methoxy)benzyl-2-benzimidazolyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 132a) EXAMPLE 119 Methyl11-(5-mercapto-1,2,4-thiadiazol-2-yl)thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 153a)

In Examples 111 through 119, the objective compounds were prepared in amanner similar to Example 109, using the corresponding 11-hydroxy- or11-methoxy-6,11-dihydrodibenz[b,e]oxepin derivative (Compounds b, f andp) and thiol compounds.

EXAMPLE 120 Methyl11-(5-octadecylthio-1,3,4-thiadiazol-2-yl)thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 154a)

After 50 ml of an N,N-dimethylformamide solution containing a mixture of2.0 g Compound 153a obtained in Example 119, 2 ml of octadecyl bromideand 2.0 g of potassium carbonate was stirred at 80° C. at 1.5 hours, thesolvent was distilled off under reduced pressure. The aqueous phase wasextracted with 200 ml of methylene chloride. The extract was washed withsaturated sodium chloride aqueous solution. After drying over anhydroussodium sulfate, the solvent was distilled off under reduced pressure.The resulting residue was subjected to silica gel column chromatography(eluting solvent; hexane:ethyl acetate=15:1) to give 0.8 g of theproduct.

EXAMPLE 121 Methyl11-phenylsulfonyl-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound157a)

Compound b, 10 g, 15 g of sodium benzenesulfinate dihydrate and 25 ml oftrifluoroacetic anhydride were treated in a manner similar to Example109 to give 14.3 g of the objective compound.

EXAMPLE 122 Methyl11-([(3-pyridyl)methyl]thio-6,11-dihydrodibenzo[b,e]thiepin-2-carboxylate(Compound 166a)

The product was prepared in a similar manner to Example 109 usingCompound q obtained in Reference Example 17 and(3-methylpyridyl)methylthiol.

Physicochemical properties of the compounds obtained in Examples 109 to122 are shown in Table 5-6.

                                      TABLE 5-6                                   __________________________________________________________________________    Example   MP °C.                                                       No.       (Solvent                                                            (Com-     for                 IR                                              pound                                                                              Appear-                                                                            recrystal-                                                                         NMR            (Method)                                                                             Elemental analysis                       No.) ance lization)                                                                          (Solvent) δ, ppm                                                                       cm.sup.-1                                                                            %                                        __________________________________________________________________________    109  color-                                                                             --   (CDCl.sub.3) 3.78(s, 3H), 5.38                                                               (neat) --                                       (8a) less      (s, 1H), 4.91 & 6.26(ABq, J=                                                                 3030, 2950,                                          oil       12.5Hz, 2H), 6.69-8.01(m,                                                                    1711, 1570,                                                    9H), 8.33(d, J=5.4Hz, 2H)                                                                    1434, 1245,                                                                   1118, 1007,                                                                    767                                            110  white                                                                              129-131                                                                              --           (KBr tablet)                                                                         C.sub.21 H.sub.17 NO.sub.3 S.C.sub.4                                          H.sub.4 O.sub.4                          (8a')                                                                              solid                                                                              (dec.)              1707, 1614,                                                                              C  H  N                                        (diethyl-           1437, 1281,                                                                          Found                                                                             62.59                                                                            4.40                                                                             2.93                                     ether)*             1241, 1005                                                                           Calcd.                                                                            62.62                                                                            4.41                                                                             2.92                           111  yellow                                                                             --   (CDCl.sub.3) 3.55(s, 2H), 3.82                                                               (CHCl.sub.3)                                                                         --                                       (14a)                                                                              amor-     (s, 3H), 4.86(s, 1H), 4.84 &                                                                 2954, 1715,                                          phous     6.36(ABq, J=13.4Hz, 2H),                                                                     1612, 1575,                                                    6.70-7.90(m, 2H), 8.35-8.58                                                                  1437, 1296,                                                    (m, 2H)        1008                                            112  color-                                                                             124-125                                                                            (CDCl.sub.3) 3.56(bs, 2H), 3.79                                                              (CHCl.sub.3)                                                                         C.sub.22 H.sub.19 NO.sub.3 S             (15a)                                                                              less (meth-                                                                             (s, 3H), 4.79(s, 1H), 4.84 &                                                                 2954, 1718,                                                                              C  H  N                                   amor-                                                                              anol)                                                                              6.18(ABq, J=12.7Hz, 2H),                                                                     1567, 1458,                                                                          Found                                                                             70.04                                                                            5.09                                                                             3.60                                phous     6.82-7.71(m, 11H), 8.27-8.65                                                                 1437, 1376,                                                                          Calcd.                                                                            70.00                                                                            5.07                                                                             3.71                                          (m, 2H)        1127, 1034                                      113  color-                                                                             --   (CDCl.sub.3) 3.66(s, 2H), 3.85(s,                                                              --   --                                       (19a)                                                                              less      3H), 4.83(s, 1H), 4.85 & 6.39                                       oil       (ABq, J=12.8Hz, 2H), 6.71-                                                    7.89(m, 12H)                                                   114  color-                                                                             --   (CDCl.sub.3) 3.50(s, 2H), 3.63(s,                                                              --   --                                       (20a)                                                                              less      2H), 3.67(s, 3H), 4.78(s,                                           oil       1H), 4.85 & 6.25(ABq, J=13.0                                                  Hz, 2H), 6.75-7.40(m, 12H)                                     115  pale --   (CDCl.sub.3) 3.51(s, 2H), 3.63(s,                                                            (neat) --                                       (126a)                                                                             yellow    3H), 4.99 & 5.89(ABq, J=13.7                                                                 2950, 1731,                                          oil       Hz, 2H), 6.47(s, 1H), 6.85-                                                                  1499, 1456,                                                    8.04(m, 11H)   1425, 1310,                                                                   1229,  757,                                                                    726                                            116  color-                                                                             --   (CDCl.sub.3) 2.53-3.25(m, 4H),                                                                 --   --                                       (129a)                                                                             less      3.74(s, 3H), 4.79(s, 1H),                                           oil       4.68 & 6.17(ABq, J=13.1Hz,                                                    2H), 6.64-7.90(m, 11H)                                         117  color-                                                                             --   (CDCl.sub.3) 2.8-3.3(m, 4H), 3.69                                                            (CHCl.sub.3)                                                                         [MS (m/z): 444 (M.sup.+)]                (130a)                                                                             less      (s, 3H), 3.86(s, 3H), 4.85 &                                                                 1714, 1611,                                          amor-     6.37(ABq, J=12.9Hz, 2H), 4.94                                                                1249, 1120,                                          phous     (s, 1H), 6.82(d, J=8.5Hz, 1H),                                                               1008                                                           7.1-7.4(m, 8H), 7.77(dd, J=                                                   2.2 & 8.5Hz, 1H), 7.89(d, J=                                                  2.2Hz, 1H)                                                     118  yellow                                                                             --   (CDCl.sub.3) 2.7-3.1(m, 4H), 3.74                                                              --   [MS (m/z): 550 (M.sup.+)]                (132a)                                                                             amor-     (s, 6H), 3.84(s, 2H), 4.84 &                                        phous     6.36(ABq, J=13.1Hz, 2H), 4.90                                                 (s, 1H), 5.23(s, 2H), 6.6-7.4                                                 (m, 13H), 7.76(dd, J=2.1 & 8.5                                                Hz, 1H), 7.90(d, J=2.1Hz, 1H)                                  119  pale --   (CDCl.sub.3) 3.84(s, 3H), 4.95 &                                                             --       --                                     (153a)                                                                             yellow    5.97(ABq, J=13.7Hz, 2H), 6.20                                       amor-     (s, 1H), 6.78-8.22(m, 7H)                                           phous                                                                    120  pale (ethyl                                                                             (CDCl.sub.3) 0.73-2.02(m, 35H),                                                                --   C.sub.36 H.sub.50 N.sub.2 O.sub.3                                             S.sub.3                                  (154a)                                                                             yellow                                                                             acetate)                                                                           3.24(t, J=6.9Hz, 2H), 3.82(s,                                                                           C  H  N                                   crystal   3H), 4.98 & 6.04(ABq, J=12.5                                                                        Found                                                                             66.21                                                                            7.66                                                                             4.27                                          Hz, 2H), 6.13(s, 1H), 6.84(d,                                                                       Calcd.                                                                            66.02                                                                            7.69                                                                             4.28                                          J=8.5Hz, 1H), 7.11-7.41(m,                                                    4H), 7.78(dd, J=2.0, 8.5Hz,                                                   1H), 8.03(d, J=2.0Hz, 1H)                                      121  white                                                                              189-191                                                                            (CDCl.sub.3) 3.78(s, 3H), 4.80 &                                                               --   C.sub.22 H.sub.18 O.sub.5 S              (157a)                                                                             solid                                                                              (diiso-                                                                            6.30(ABq, J=13.2Hz, 2H), 5.25                                                                            C H                                           propyl-                                                                            (s, 1H), 6.63-7.97(m, 12H)                                                                          Found                                                                             66.85                                                                            4.61                                        ether)*                    Calcd.                                                                            66.99                                                                            4.60                              122  pale --   (CDCl.sub.3) 3.62(s, 2H), 3.89(s,                                                              --   [MS (m/z): 393 (M.sup.+)]                (166a)                                                                             yellow    3H), 5.08(s, 1H), 5.3-5.8(b,                                        oil       2H), 7.0-7.35(m, 6H), 7.5-                                                    7.7(m, 2H), 7.82(bs, 1H),                                                     8.38(bs, 1H), 8.45(d, J=8.0                                                   Hz, 1H)                                                        __________________________________________________________________________

EXAMPLE 12311-(4-Pyridyl)thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid(Compound 8b) EXAMPLE 12411-[(3-Pyridyl)methyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound 14b) EXAMPLE 12511-[(3-Pyridyl)methyl]thio-6,11-dihydrodibenz[b,e]oxepin-3-carboxylicacid (Compound 15b) EXAMPLE 126 Sodium11-[(3-pyridyl)methyl]thio-6,11-dihydrodibenz[b,e]oxepin-3-carboxylate(Compound 15b') EXAMPLE 12711-(Benzyl)thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid(Compound 19b) EXAMPLE 12811-(Benzyl)thio-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid (Compound20b) EXAMPLE 12911-[2-(2-Benzimidazolyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid 1.5 hydrate (Compound 129b') EXAMPLE 13011-[2-(1-Methyl-2-benzimidazolyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound 130b) EXAMPLE 13111-Phenylsulfonyl-6,11-dihydrodibenz[b,e]oxepin- 2-carboxylic acid(Compound 157b) EXAMPLE 13211-[(3-Pyridyl)methyl]thio-6,11-dihydrodibenzo[b,e]thiepin-2-carboxylicacid (Compound 166b)

In Examples 123 through 132, the objective compounds were prepared byhydrolyzing esters of the corresponding oxepine or thiepine derivativesin a manner similar to Example 14 or 15.

Compound 15b' in Example 126 was treated in a manner similar to Example62 to give the product as the sodium salt.

Physicochemical properties of the compounds obtained in Examples 123 to132 are shown in Table 5-7.

                                      TABLE 5-7                                   __________________________________________________________________________    Example   MP °C.                                                       No.       (Solvent                                                            (Com-     for                 IR                                              pound                                                                              Appear-                                                                            recrystal-                                                                         NMR            (Method)                                                                             Elemental analysis                       No.) ance lization)                                                                          (Solvent) δ, ppm                                                                       cm.sup.-1                                                                            %                                        __________________________________________________________________________    123  white                                                                              217-218                                                                            (DMSO-d.sub.6) 5.15 & 6.23(ABq,                                                              (KBr tablet)                                                                         C.sub.20 H.sub.15 NO.sub.3 S             (8b) solid                                                                              (dec.)                                                                             J=12.9Hz, 2H), 6.29(s, 1H),                                                                  1671, 1582,                                                                              C  H  N                                        (isopro-                                                                           6.94(d, J=8.5Hz, 1H), 7.23-                                                                  1496, 1409,                                                                          Found                                                                             68.58                                                                            4.27                                                                             3.83                                     panol)                                                                             7.52(m, 6H), 7.76(dd, J=2.2,                                                                 1296, 1032                                                                           Calcd.                                                                            68.75                                                                            4.33                                                                             4.01                                          8.5Hz, 1H), 8.11(d, J=2.2Hz,                                                                 1011                                                           1H), 8.42(d, J=4.4Hz, 2H)                                      124  white                                                                              233-235                                                                            (DMSO-d.sub.6) 3.67 & 3.78(ABq,                                                                --   C.sub.21 H.sub.17 NO.sub.3 S             (14b)                                                                              solid                                                                              (diethyl-                                                                          J=13.6Hz, 2H), 4.95 & 6.13                                                                              C  H  N                                        ether)*                                                                            (ABq, J=12.7Hz, 2H), 5.23(s,                                                                        Found                                                                             69.56                                                                            4.65                                                                             3.56                                          1H), 6.68(d, J=8.4Hz, 1H),                                                                          Calcd.                                                                            69.40                                                                            4.71                                                                             3.85                                          7.28-7.41(m, 6H), 7.65(dd,                                                    J=1.9, 8.4Hz, 1H), 7.80(d,                                                    J=1.9Hz, 1H), 8.41(bs, 2H)                                     125  white                                                                              107-110                                                                            (DMSO-d.sub.6) 3.75 & 3.83(ABq,                                                              (KBr tablet)                                                                         C.sub.21 H.sub.17 NO.sub.3 S             (15b)                                                                              solid                                                                              (water)*                                                                           J=13.4Hz, 2H), 5.02 & 6.09                                                                   2886, 1696,                                                                              C  H  N                                             (ABq, J=13.1Hz, 2H), 5.30(s,                                                                 1565, 1454,                                                                          Found                                                                             69.31                                                                            4.85                                                                             3.66                                          1H), 7.29-7.68(m, 9H), 8.43-                                                                 1415, 1191,                                                                          Calcd.                                                                            69.40                                                                            4.71                                                                             3.85                                          8.44(m, 2H), 13.01(bs, 1H)                                                                   1095, 1028                                      126  white                                                                              Imposs-                                                                              --             --   --                                       (15b')                                                                             solid                                                                              ible to                                                                       measure                                                                       due to                                                                        hygro-                                                                        scopic                                                                        nature                                                              127  white                                                                              211-212                                                                            (DMSO-d.sub.6) 3.65 & 3.84(ABq,                                                              (KBr tablet)                                                                         C.sub.22 H.sub.18 O.sub.3 S              (19b)                                                                              crystal                                                                            (toluene)                                                                          J=12.9Hz, 2H), 5.06 & 6.23                                                                   1682, 1608,                                                                               C H                                                (ABq, J=12.8Hz, 2H), 5.32(s,                                                                 1454, 1428,                                                                          Found                                                                             72.92                                                                            4.83                                             1H), 6.87(d, J=8.5Hz, 1H),                                                                   1407, 1298,                                                                          Calcd.                                                                            72.90                                                                            5.01                                             7.24-7.49(m, 9H), 7.71(dd,                                                                   1254, 1108,                                                    J=2.2 & 8.5Hz, 1H), 7.87(d,                                                                  1009,  715                                                     J=2.2Hz, 1H)                                                   128  white                                                                              125-127                                                                            (DMSO-d.sub.6) 3.45(s, 2H), 3.64 &                                                           (KBr tablet)                                                                         C.sub.23 H.sub.20 O.sub.3 S              (20b)                                                                              crystal                                                                            (toluene)                                                                          3.79(ABq, J=13Hz, 2H), 4.95                                                                  3450, 3022,                                                                              C  H                                                & 6.07(ABq, J=12.9Hz, 2H),                                                                   1694, 1499,                                                                          Found                                                                             73.11                                                                            5.56                                             5.08(s, 1H), 6.75(d, J=8.1Hz,                                                                1313, 1203,                                                                          Calcd.                                                                            73.38                                                                            5.35                                             1H), 7.03-7.41(m, 11H)                                                                       1123, 1019,                                                                    799,  759                                      129  white                                                                              164-166                                                                            (DMSO-d.sub.6) 2.87-3.36(m, 4H),                                                             (KBr tablet)                                                                         C.sub.24 H.sub.20 N.sub.2 O.sub.3                                             S.1.5H.sub.2 O                           (129b')                                                                            crystal                                                                            (isopro-                                                                           5.04 & 6.22(ABq, J=12.7Hz,                                                                   1611, 1577,                                                                              C   H N                                        panol)                                                                             2H), 5.43(s, 1H), 6.86(d, J=                                                                 1379, 1367,                                                                          Found                                                                             65.34                                                                            5.18                                                                             6.07                                          8.5Hz, 1H), 7.11-7.51(m, 8H),                                                                1252, 1226,                                                                          Calcd.                                                                            64.99                                                                            5.23                                                                             6.32                                          7.70(dd, J=2.2 & 8.5Hz, 1H),                                                                 1007,  761                                                     8.00(d, J=2.2Hz, 1H)                                           130  white                                                                              207-208                                                                            (DMSO-d.sub.6) 3.72(s, 3H), 5.04                                                             (KBr tablet)                                                                         C.sub.25 H.sub.22 N.sub.2 O.sub.3 S      (130b)                                                                             crystal                                                                            (isopro-                                                                           & 6.24(ABq, J=12.7Hz, 2H),                                                                   1695, 1615,                                                                              C  H  N                                        panol)                                                                             5.51(s, 1H), 6.89(d, J=8.5Hz,                                                                1231, 1007                                                                           Found                                                                             69.78                                                                            5.11                                                                             6.38                                          1H), 7.11-7.23(m, 2H), 7.35-                                                                        Calcd.                                                                            69.75                                                                            5.15                                                                             6.51                                          7.58(m, 6H), 7.71(dd, J=2.2                                                   & 8.5Hz, 1H), 8.02(d, J=2.2                                                   Hz, 1H)                                                        131  white                                                                              233  (CDCl.sub.3 +DMSO-d.sub.6) 4.92 &                                                              --   C.sub.21 H.sub.16 O.sub.5 S              (157b)                                                                             crystal                                                                            (dec.)                                                                             6.35(ABq, J=13.1Hz, 2H), 5.85                                                                           C  H                                           (isopro-                                                                           (s, 1H), 6.90-8.07(m, 12H)                                                                          Found                                                                             66.20                                                                            4.25                                        panol)                     Calcd.                                                                            66.30                                                                            4.24                              132  pale 226-227.5                                                                            --           (KBr tablet)                                                                         C.sub.21 H.sub.17 NO.sub.2 S.sub.2       (166b)                                                                             yellow                                                                             (meth-              1678, 1594,                                                                              C  H  N                                   crystal                                                                            anol)               1553, 1280,                                                                          Found                                                                             66.46                                                                            4.44                                                                             3.58                                                         1130, 1048                                                                           Calcd.                                                                            66.47                                                                            4.52                                                                             3.69                           __________________________________________________________________________

EXAMPLE 133 Methyl(E)-11-[2-[(2-pyridyl)thio]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-138a)

In 100 ml of N,N-dimethylformamide were stirred 2.0 g of methyl(E)-11-(2-chloroethylidene)-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound h) obtained in Reference Example 8 and 1.1 g of2-mercaptopyridine at 60° C. for 1.5 hours. The solvent was distilledoff under reduced pressure. The obtained residue was extracted with 200ml of ethyl acetate. The extract was washed successively with saturatedsodium bicarbonate aqueous solution and saturated sodium chlorideaqueous solution. After drying over anhydrous magnesium sulfate, thesolvent was distilled off under reduced pressure. The resulting residuewas subjected to silica gel column chromatography (eluting solvent;hexane:ethyl acetate=5:1) to give 2.4 g of the product.

EXAMPLE 134 Methyl(E)-11-[2-[(2-pyrimidyl)thio]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-139a) EXAMPLE 135 Methyl(E)-11-[2-[(2-quinolyl)thio]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-140a) EXAMPLE 136 Methyl (E)-11-[2-[3-hydroxy-2-pyridyl)thio]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-141a) EXAMPLE 137 Methyl(E)-11-[2-[(4-methyl-4H-1,2,4-triazol-3-yl)thio]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-156a)

In Examples 134 through 137, the objective compounds were prepared usingCompound h and the corresponding thiol compounds in a manner similar toExample 133.

Physicochemical properties of the compounds obtained in examples 133 to137 are shown in Table 5-8.

                                      TABLE 5-8                                   __________________________________________________________________________    Example   MP °C.                                                       No.       (Solvent                                                            (Com-     for                 IR                                              pound                                                                              Appear-                                                                            recrystal-                                                                         NMR            (Method)                                                                             Elemental analysis                       No.) ance lization)                                                                          (Solvent) δ, ppm                                                                       cm.sup.-1                                                                            %                                        __________________________________________________________________________    133  color-                                                                             --   (CDCl.sub.3) 3.84(s, 3H), 3.92                                                               --     --                                       (E-138a)                                                                           less      (d, J=7.9Hz, 2H), 4.64-5.52                                         oil       (b, 2H), 6.21(t, J=7.9Hz, 1H),                                                6.61-8.32(m, 11H)                                              134  color-                                                                             --   (CDCl.sub.3) 3.81(s, 3H), 3.90(d,                                                            --     --                                       (E-139a)                                                                           less      J=7.7Hz, 2H), 4.60-5.65(b,                                          oil       2H), 6.29(t, J=7.7Hz, 1H),                                                    6.61-8.04(m, 8H), 8.37(d, J=                                                  5.6Hz, 2H)                                                     135  --   --   (CDCl.sub.3) 3.79(s, 3H), 4.10(d,                                                            --     --                                       (E-140a)       J=7.4Hz, 2H), 4.56-5.58(b,                                                    2H), 6.31(t, J=7.4Hz, 1H),                                                    6.66-8.06(m, 13H)                                              136  pale 142-144                                                                            (CDCl.sub.3) 3.86(s, 3H), 4.6-5.6                                                            (KBr tablet)                                                                         C.sub.23 H.sub.19 NO.sub.4 S             (E-141a)                                                                           yellow                                                                             (toluene)                                                                          (b, 2H), 6.25(t, J=7.0Hz, 1H),                                                               1682, 1445 C  H  N                                   crystal   6.83(d, J=8.5Hz, 1H), 7.0-8.1                                                                1305, 1247,                                                                          Found                                                                             68.01                                                                            4.88                                                                             3.51                                          (m, 9H)        1129, 999                                                                            Calcd.                                                                            68.13                                                                            4.72                                                                             3.45                           137  color-                                                                             --   (CDCl.sub.3) 3.41(s, 3H), 3.78(s,                                                            --     --                                       (E-156a)                                                                           less      3H), 4.62-5.53(m, 4H), 6.21                                         oil       (t, J=7.9Hz, 1H), 6.60-7.94                                                   (m, 7H), 8.05(s, 1H)                                           __________________________________________________________________________

EXAMPLE 138(E)-11-[2-[(2-Pyridyl)thio]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound E-138b) EXAMPLE 139(E)-11-[2-[(2-Pyrimidyl)thio]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound E-139b) EXAMPLE 140(E)-11-[2-[(2-Quinolyl)thio]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound E-140b) EXAMPLE 141(E)-11-[2-[(3-Hydroxy-2-pyridyl)thio]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound E-141b) EXAMPLE 142(E)-11-[2-[(4-Methyl-4H-1,2,4-triazol-3-yl)thio]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound E-156b)

In Examples 138 through 142, the products were prepared by hydrolyzingesters of the corresponding oxepine derivatives in a manner similar toExample 14 or 15.

Physicochemical properties of the compounds obtained in Examples 138 to142 are shown in Table 5-9.

                                      TABLE 5-9                                   __________________________________________________________________________    Example   MP °C.                                                       No.       (Solvent                                                            (Com-     for                 IR                                              pound                                                                              Appear-                                                                            recrystal-                                                                         NMR            (Method)                                                                             Elemental analysis                       No.) ance lization)                                                                          (Solvent) δ, ppm                                                                       cm.sup.-1                                                                            %                                        __________________________________________________________________________    138  white                                                                              242-243                                                                            (DMSO-d.sub.6) 3.84-3.93(m, 2H),                                                             (KBr tablet)                                                                         C.sub.22 H.sub.17 NO.sub.3 S             (E-138b)                                                                           crystal                                                                            (isopro-                                                                           5.01&5.36(each bs, 2H),                                                                      1684, 1602,                                                                              C  H  N                                        panol)                                                                             6.21(t, J=7.8Hz, 1H), 6.81(d,                                                                1454, 1435,                                                                          Found                                                                             70.30                                                                            4.55                                                                             3.35                                          J=8.5Hz, 1H), 7.08-7.65(m,                                                                   1418, 1315,                                                                          Calcd.                                                                            70.38                                                                            4.56                                                                             3.73                                          7H), 7.71(dd, J=2.2, 8.5Hz,                                                                  1262, 995,                                                     1H), 7.84(d, J=2.2Hz, 1H),                                                                   756                                                            8.29-8.31(m, 1H), 12.73(bs,                                                   1H)                                                            139  yellow                                                                             250-253                                                                            (DMSO-d.sub.6) 3.80-3.87(m, 2H),                                                             (KBr tablet)                                                                         C.sub.21 H.sub.16 N.sub.2 O.sub.3 S      (E-139b)                                                                           crystal                                                                            (isopro-                                                                           5.04&5.45(each bs, 2H),                                                                      1690, 1605,                                                                              C  H  N                                        panol)                                                                             6.24(t, J= 7.7Hz, 1H), 6.82(d,                                                               1568, 1553                                                                           Found                                                                             66.98                                                                            4.42                                                                             7.52                                          J=8.6Hz, 1H), 7.19-7.60(m,                                                                   1408, 1382,                                                                          Calcd.                                                                            67.01                                                                            4.28                                                                             7.44                                          5H), 7.71(dd, J=2.1, 8.6Hz,                                                                  1248, 1194,                                                    1H), 7.86(d, J=2.2Hz, 1H),                                                                   1003, 754,                                                     8.56(d, J=4.9Hz, 2H)                                                                         731                                             140  yellow                                                                             225-228                                                                            --             (KBr tablet)                                                                         C.sub.26 H.sub.19 NO.sub.3 S             (E-140b)                                                                           crystal                                                                            (dec.)              3450, 1693,                                                                              C  H  N                                        (isopro-            1602, 1591,                                                                          Found                                                                             73.38                                                                            4.52                                                                             3.37                                     panol)              1496, 1311,                                                                          Calcd.                                                                            73.39                                                                            4.50                                                                             3.29                                                         1259, 1135,                                                                   1088, 1001,                                                                   810                                             141  pale 201.5-203                                                                          (DMSO-d.sub.6) 3.65(m, 2H), 5.02                                                             (KBr tablet)                                                                         C.sub.22 H.sub.17 NO.sub.4 S             (E-141b)                                                                           yellow                                                                             (aceto-                                                                            &5.43(each bs, 2H), 6.20                                                                     1678, 1605,                                                                              C  H  N                                   crystal                                                                            nitrile)                                                                           (t, J=7.8Hz, 1H), 6.81(d, J=                                                                 1441, 1294,                                                                          Found                                                                             67.88                                                                            4.23                                                                             3.81                                          8.5Hz, 1H), 6.95-7.10(m, 2H),                                                                1264, 1241,                                                                          Calcd.                                                                            67.50                                                                            4.38                                                                             3.58                                          7.35-7.60(m, 4H), 7.71(dd,                                                                   1003                                                           J=2.2&8.5Hz, 1H), 7.80-7.85                                                   (m, 2H), 10.40(s, 1H)                                          142  white                                                                              236-237                                                                            (DMSO-d.sub.6) 3.35(s, 3H), 3.80-                                                            (KBr tablet)                                                                         C.sub.20 H.sub.17 N.sub.3 O.sub.3 S      (E-156b)                                                                           crystal                                                                            (isopro-                                                                           3.84(m, 2H), 4.88&5.14                                                                       1670, 1607,                                                                              C  H  N                                        panol)                                                                             (each bs, 2H), 6.20(t, J=7.9                                                                 1484, 1426,                                                                          Found                                                                             63.28                                                                            4.55                                                                             11.22                                         Hz, 1H), 6.81(d, J=8.5Hz, 1H),                                                               1318, 1242,                                                                          Calcd.                                                                            63.31                                                                            4.52                                                                             11.07                                         7.2-7.5(m, 4H), 7.72(dd, J=                                                                  1198, 1014,                                                    2.2, 8.5Hz, 1H), 7.84(d, J=                                                                  770, 755                                                       2.2Hz, 1H), 8.51(s, 1H)                                        __________________________________________________________________________

EXAMPLE 143 Methyl11-[2-(1-benzimidazolyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 45a)

The objective compound was prepared in a manner similar to Example 23,using 1.6 g of methyl11-(2-iodoethyl)thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound n) obtained in Reference Example 14 and 1.4 g ofbenzimidazole.

EXAMPLE 144 Methyl11-[2-[(1,2,3,4-tetrahydroisoquinolin)-2-yl]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 158a)

In a solvent mixture of 200 ml of ethanol and 50 mol of dioxane wereheated to reflux 6.0 g of Compound n and 10 ml of1,2,3,4-tetrahydroisoquinolin for 4.5 hours. After allowing to cool, thesolvent was distilled off under reduced pressure. The obtained residuewas extracted with 500 ml of methylene chloride and washed successivelywith saturated sodium bicarbonate aqueous solution and saturated sodiumchloride aqueous solution. After drying over anhydrous magnesiumsulfate, the solvent was distilled off under reduced pressure. Theresulting residue was subjected to silica gel column chromatography(eluting solvent; hexane:ethyl acetate:triethylamine=50:10:5) to give5.2 g of the product.

EXAMPLE 145 Methyl11-[2-[(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin)-2-yl]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 161a)

The objective compound was prepared in a manner similar to Example 144,using Compound n and the corresponding isoquinoline derivative.

EXAMPLE 146 Methyl(Z,E)-11-[3-[(1,2,3,4-tetrahydroisoquinolin)-2-yl]propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 162a)

The objective compound was prepared in a manner similar to Example 144,using Compound ma nd the corresponding isoquinoline derivative.

Physicochemical properties of the compounds obtained in Examples 143 to146 are shown in Table 5-10.

                                      TABLE 5-10                                  __________________________________________________________________________    Example   MP °C.                                                       No.       (Solvent                                                            (Com-     for                  IR                                             pound                                                                              Appear-                                                                            recrystal-                                                                         NMR             (Method)                                                                            Elemental analysis                       No.) ance lization)                                                                          (Solvent) δ, ppm                                                                        cm.sup.-1                                                                           %                                        __________________________________________________________________________    143  pale --   (CDCl.sub.3) 2.79(t, J=6.9Hz, 2H),                                                            --    --                                       (45a)                                                                              yellow    3.82(s, 3H), 4.01(t, J=6.9Hz,                                       amor-     2H), 4.76(s, 1H), 4.76&                                             phous     6.25(ABq, J=12.8Hz, 1H), 6.64-                                                7.91(m, 11H)                                                   144  yellow                                                                             --   (CDCl.sub.3) 2.20-3.03(m, 8H),                                                                (neat)                                                                              --                                       (158a)                                                                             oil       3.57(s, 2H), 3.83(s, 3H),                                                                     3400, 2948,                                                   5.10(s, 1H), 4.86&6.47(ABq,                                                                   2800, 1718,                                                   J=12.7Hz, 2H), 6.75-8.06(m,                                                                   1611, 1497,                                                   11H)            1435, 1244,                                                                   1118, 1008,                                                                   769, 741                                       145  color-                                                                             --   (CDCl.sub.3) 2.68-3.77(m, 8H),                                                                --    --                                       (161a)                                                                             less      3.78(s, 6H), 3.81(s, 3H),                                           oil       4.38(bs, 2H), 4.98&6.28                                                       (ABq, J=11.5Hz, 2H), 5.56(s,                                                  1H), 6.58-8.14(m, 9H)                                          146  color-                                                                             --   (CDCl.sub.3 ) 2.41-2.92(m, 8H),                                                               (neat)                                                                              --                                       (162a)                                                                             less      3.57(bs, 2H), 3.79(s, 2H),                                                                    2948, 2922,                                         oil       5.14(bs, 2H), 5.73(bs, 1H),                                                                   1711, 1607,                                                   7.59-7.99(m, 11H)                                                                             1488, 1435,                                                                   1239, 1130,                                                                   1118, 1004,                                                                   767                                            __________________________________________________________________________

EXAMPLE 14711-[2-(1-Benzimidazolyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate·monohydrochloride(Compound 45b')

Compound 45a, 0.85 g, obtained in example 143 was hydrolyzed in a mannersimilar to Example 15. By adjusting pH to 1.8, the hydrochloride of theproduct was precipitated and collected.

EXAMPLE 14811-[2[(1,2,3,4-Tetrahydroisoquinolin)-2-yl]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate·1.8hydrate (Compound 158b') EXAMPLE 14911-[2-[(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolin)-2-yl]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate·1.5hydrate (Compound 161b')

In Examples 148 and 149, the objective compound was prepared byhydrolyzing esters of the corresponding oxepin derivative in a mannersimilar to Example 14 or 15.

EXAMPLE 150(Z,E)-11-[3-[(1,2,3,4-Tetrahydroisoquinolin)-2-yl]propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate·monohydrochloride(Compound 162b')

Compound 162a (Z/E=7/3), 2.1 g obtained in Example 146 was hydrolyzed ina manner similar to Example 15. By adjusting pH to 1.0, the objectivecompound was precipitated as the hydrochloride and collected byfiltration. The crude product was recrystallized from isopropanol twiceto give 0.9 g of the objective compound (Z/E=9/1).

Physicochemical properties of the compounds obtained in Examples 147 to150 are shown in Table 5-11.

                                      TABLE 5-11                                  __________________________________________________________________________    Example   MP °C.                                                       No.       (Solvent                                                            (Com-     for                  IR                                             pound                                                                              Appear-                                                                            recrystal-                                                                          NMR            (Method)                                                                             Elemental analysis                      No.) ance lization)                                                                           (Solvent) δ, ppm                                                                       cm.sup.-1                                                                            %                                       __________________________________________________________________________    147  white                                                                              230-231.5                                                                           (DMSO-d.sub.6) 2.99(t, J=6.7Hz,                                                              (KBr tablet)                                                                         C.sub.24 H.sub.20 N.sub.2 O.sub.3                                             S.HCl                                   (45b')                                                                             crystal                                                                            (dec.)                                                                              2H), 4.61-4.74(m, 2H), 4.99                                                                  1698, 1608,                                                                              C  H  N                                       (aceto-                                                                             &6.14(ABq, J=12.8Hz, 2H),                                                                    1499, 1446,                                                                          Found                                                                             63.59                                                                            4.64                                                                             6.29                                    nitrile)                                                                            5.65(s, 1H), 6.87(d, J=8.6                                                                   1236, 1202,                                                                          Calcd.                                                                            63.64                                                                            4.67                                                                             6.18                                          Hz, 1H), 7.34-7.94(m, 9H),                                                                   1114, 1005,                                                    8.05(d, J=2.0Hz, 1H), 9.34(s,                                                                759                                                            1H)                                                           148  yellow                                                                             139-141                                                                             (DMSO-d.sub.6) 2.50-3.78(m, 10H),                                                            (KBr tablet)                                                                         C.sub.26 H.sub.25 NO.sub.3 S.1.8H.su                                          b.2 O                                   (158b')                                                                            powder                                                                             (isopropyl                                                                          5.06&6.25(ABq, J=12.7Hz,                                                                     3450, 2930,                                                                              C  H  N                                       ether)                                                                              2H), 5.50(s, 1H), 6.87-8.02                                                                  1700, 1608,                                                                          Found                                                                             67.06                                                                            6.00                                                                             3.04                                          (m, 11H)       1232, 1107,                                                                          Calcd.                                                                            67.31                                                                            6.21                                                                             3.02                                                         1007, 750                                      149  white                                                                              112-113                                                                             (DMSO-d.sub.6) 2.50-2.65(m, 6H),                                                             (KBr tablet)                                                                         C.sub.28 H.sub.29 NO.sub.5 S.1.5H.su                                          b.2 O                                   (161b')                                                                            crystal                                                                            (isopro-                                                                            3.43-3.69(m, 2H), 3.69(s,                                                                    2930, 1610,                                                                              C  H  N                                       panol)                                                                              3H), 3.70(s, 3H), 3.80-3.95                                                                  1519, 1456,                                                                          Found                                                                             64.96                                                                            6.22                                                                             2.45                                          (m, 2H), 5.05&6.28(ABq, J=                                                                   1371, 1229,                                                                          Calcd.                                                                            64.85                                                                            6.22                                                                             2.70                                          12.7Hz, 2H), 5.48(s, 1H),                                                                    1122, 1009,                                                    6.58(s, 1H), 6.64(s, 1H),                                                                    787                                                            6.87(d, J=8.5Hz, 1H), 7.37-                                                   7.48(m, 4H), 7.71(dd, J=2.2&                                                  8.5Hz, 1H), 7.99(d, J=2.2Hz,                                                  1H)                                                           150  white                                                                              253-254                                                                             --             --     C.sub.27 H.sub.25 NO.sub.3 S HCl        (162b')                                                                            crystal                                                                            (dec.)                          C  H  N                                       (isopro-                    Found                                                                             72.30                                                                            5.96                                                                             3.01                                    panol)                      Calcd.                                                                            72.39                                                                            5.85                                                                             3.13                          __________________________________________________________________________

EXAMPLE 151 Methyl11-[(3-pyridyl)methyl]oxy-6,11-dihydrodibenz[b,e]oxepin-2,-carboxylate(Compound 21a) EXAMPLE 152 Methyl11-[(3-pyridyl)ethyl]oxy-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 22a) EXAMPLE 153 Methyl 11-[2-[(2-hydroxy)phenyl]ethyloxy-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound 165a)

In Examples 151 through 153, the objective compounds were prepared in amanner similar to Example 1, using methyl11-hydroxy-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound b)obtained in Reference Example 2 and the corresponding alcohol compounds.

Physicochemical properties of the compounds obtained in examples 151 to153 are shown in Table 5-12.

                                      TABLE 5-12                                  __________________________________________________________________________    Example   MP °C.                                                       No.       (Solvent                                                            (Com-     for                 IR                                              pound                                                                              Appear-                                                                            recrystal-                                                                         NMR            (Method)                                                                             Elemental analysis                       No.) ance lization)                                                                          (Solvent) δ, ppm                                                                       cm.sup.-1                                                                            %                                        __________________________________________________________________________    151  white                                                                              unclear                                                                            (CDCl.sub.3) 3.83(s, 3H), 4.48(s,                                                            (KBr tablet)                                                                         C.sub.22 H.sub.19 NO.sub.4               (21a)                                                                              solid                                                                              (isopro-                                                                           2H), 5.20(s, 1H), 4.87&                                                                      1717, 1609,                                                                              C  H  N                                        panol)                                                                             6.14(ABq, J=12Hz, 2H), 6.73-                                                                 1252, 1124,                                                                          Found                                                                             73.15                                                                            5.30                                                                             3.70                                          8.01(m, 9H), 8.31-8.60(m, 2H)                                                                1030, 1012,                                                                          Calcd.                                                                            73.12                                                                            5.30                                                                             3.88                                                         769                                             152  color-                                                                             --   (CDCl.sub.3) 3.02(t, J=6.5Hz, 2H),                                                           (neat) --                                       (22a)                                                                              less      3.84(t, J=6.5Hz, 2H), 3.81(s,                                                                1716, 1613,                                          oil       3H), 5.11(s, 1H), 4.70&5.86                                                                  1436, 1290,                                                    (ABq, J=12.2Hz, 2H), 6.69-                                                                   1245, 1006,                                                    8.02(m, 10H), 8.31-8.50(m,                                                                   769                                                            1H)                                                            153  yellow                                                                             --   (CDCl.sub.3) 2.86(t, J=5.4Hz, 2H),                                                           (CHCl.sub.3)                                                                         --                                       (165a)                                                                             oil       3.42-3.90(m, 2H), 3.82(s,                                                                    3270, 1715,                                                    3H), 4.78&5.92(ABq, J=12.0                                                                   1615, 1490,                                                    Hz, 2H), 5.15(s, 1H), 6.58-                                                                  1295, 1253,                                                    7.98(m, 11H)   1122, 1006                                      __________________________________________________________________________

EXAMPLE 15411-[(3-Pyridyl)methyl]oxy-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid·dihydrate (Compound 21b') EXAMPLE 155 Sodium11-[(3-pyridyl)ethyl]oxy-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid·monohydrate (Compound 22b') EXAMPLE 15611-[2-[(2-Hydroxy)phenyl]ethyl]oxy-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid·0.2 isopropyl ether (Compound 165b')

In Examples 154 through 156, the objective compounds were prepared byhydrolyzing esters of the corresponding oxepine derivatives in a mannersimilar to Example 14 or 15.

Compound 22b' in Example 155 was treated in a manner similar to Example62 to give the product as the sodium salt.

Physicochemical properties of the compounds obtained in Examples 154 to156 are shown in Table 5-13.

                                      TABLE 5-13                                  __________________________________________________________________________    Example   MP °C.                                                       No.       (Solvent                                                            (Com-     for                  IR                                             pound                                                                              Appear-                                                                            recrystal-                                                                          NMR            (Method)                                                                             Elemental analysis                      No.) ance lization)                                                                           (Solvent) δ, ppm                                                                       cm.sup.-1                                                                            %                                       __________________________________________________________________________    154  white                                                                              (isopro-                                                                            (DMSO-d.sub.6) 4.45&4.56(ABq,                                                                (KBr tablet)                                                                         C.sub.21 H.sub.17 NO.sub.4.2H.sub.2                                           O                                       (21b')                                                                             crystal                                                                            panol)                                                                              J=11.8Hz, 2H), 4.98&5.98                                                                     1615, 1584,                                                                              C  H  N                                             (ABq, J=12.1Hz, 2H), 5.46(s,                                                                 1541, 1394,                                                                          Found                                                                             65.58                                                                            5.20                                                                             3.52                                          1H), 6.72(d, J=8.4Hz, 1H),                                                                   1256, 1232,                                                                          Calcd.                                                                            65.79                                                                            5.52                                                                             3.65                                          7.31-7.69(m, 6H), 7.75(dd,                                                                   1136, 1049,                                                    J=1.9, 8.3Hz, 1H), 7.95(d,                                                                   1008                                                           J=1.9Hz, 1H), 8.47(bs, 2H)                                    155  white                                                                              unclear                                                                             --             (KBr tablet)                                                                         C.sub.22 H.sub.18 NO.sub.4 Na.H.sub.                                          2 O                                     (22b')                                                                             solid                                                                              (isopropyl           1614, 1590,                                                                              C  H  N                                       ether)*              1549, 1393,                                                                          Found                                                                             65.45                                                                            4.80                                                                             3.54                                                         1254, 1230,                                                                          Calcd.                                                                            65.83                                                                            5.02                                                                             3.49                                                         1111, 1072,                                                                   1008                                           156  yellow                                                                             110-120                                                                             (CDCl.sub.3) 2.90-2.94(m, 2H),                                                               --     C.sub.23 H.sub.20 O.sub.5.0.2C.sub.6                                           H.sub.14 O                             (165b')                                                                            powder                                                                             (unclear)                                                                           3.62-3.81(m, 2H), 4.86&   C  H                                          (isopro-                                                                            5.98(ABq, J=12.4Hz, 2H), 5.22                                                                       Found                                                                             73.55                                                                            5.84                                       pyl ether-                                                                          (s, 1H), 6.79-7.42(m, 9H),                                                                          Calcd.                                                                            73.24                                                                            5.79                                       hexane)                                                                             7.96(dd, J=2.2, 8.7Hz, 1H),                                                   8.07(d, J=2.2Hz, 1H)                                          __________________________________________________________________________

EXAMPLE 157 Methyl11-[(3-pyridyl)methyl]imino-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 25a)

To 150 ml of a dry benzene solution containing a mixture of 5.0 g ofmethyl 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound a)obtained in Reference Example 1, 13 ml of 3-aminomethylpyridine and 15.8ml of dicyclohexylmethylamine was dropwise added 50 ml of a dry benzenesolution containing 4.1 ml of titanium tetrachloride. After heating toreflux of 3.5 hours, saturated sodium bicarbonate aqueous solution wasadded to the reaction mixture followed by stirring. Insoluble matterswere filtered off and the filtrate was extracted with 300 ml of ethylacetate. The extract was washed successively with saturated sodiumbicarbonate aqueous solution and saturated sodium chloride aqueoussolution. After drying over anhydrous magnesium sulfate, the solvent wasdistilled off under reduced pressure. The resulting residue wassubjected to silica gel column chromatography (eluting solvent;hexane:ethyl acetate:triethylamine=10:5:1) to give 1.7 g of the crudeproduct. The obtained crude product was recrystallized from isopropylether to give 1.3 g of the product.

EXAMPLE 158 Methyl 11-(3-pyridyl)imino-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound 23a) EXAMPLE 159Methyl 11-(3-pyridyl)imino-6,11-dihydrodibenz[b,e]oxepin-2-acetate(compound 24a) EXAMPLE 160 Methyl11-[2-(2-pyridyl)ethyl]imino-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 28a) EXAMPLE 161 Methyl11-[2-(1-methylpyrrol-2-yl)ethyl]imino-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 29a)

In Examples 158 through 161, the objective compounds were prepared in amanner similar to Example 157, using the corresponding11-oxo-6,11-dihydrodibenz[b,e]oxepin derivative (Compounds a and e) andamino compounds.

Physicochemical properties of the compounds obtained in Examples 157 to161 are shown in Table 5-14.

                                      TABLE 5-14                                  __________________________________________________________________________    Example   MP °C.                                                       No.       (Solvent                                                            (Com-     for                  IR                                             pound                                                                              Appear-                                                                            recrystal-                                                                          NMR            (Method)                                                                             Elemental analysis                      No.) ance lization)                                                                           (Solvent) δ, ppm                                                                       cm.sup.-1                                                                            %                                       __________________________________________________________________________    157  white                                                                              111-112                                                                             (CDCl.sub.3) 3.85(s, 3H), 4.79                                                               (KBr tablet)                                                                         C.sub.22 H.sub.18 N.sub.2 O.sub.3       (25a)                                                                              crystal                                                                            (isopropyl                                                                          (bs, 2H), 5.14(bs, 2H), 6.73-                                                                1715, 1610,                                                                              C  H  N                                       ether)                                                                              8.05(m, 9H), 8.33-8.66(m,                                                                    1490, 1435,                                                                          Found                                                                             73.70                                                                            5.00                                                                             7.70                                          2H)            1250, 1120,                                                                          Calcd.                                                                            73.73                                                                            5.06                                                                             7.82                                                         1005, 765                                      158  color-                                                                             129.5-131                                                                           (CDCl.sub.3) 3.89(s, 3H), 5.27                                                               (CHCl.sub.3)                                                                         C.sub.21 H.sub.16 N.sub.2 O.sub.3       (23a)                                                                              less (isopropyl                                                                          (s, 2H), 6.62-8.22(m, 10H),                                                                  2925, 1718,                                                                              C  H  N                                  crystal                                                                            ether)                                                                              8.62-8.76(m, 1H)                                                                             1608, 1580,                                                                          Found                                                                             73.20                                                                            4.88                                                                             8.30                                                         1410, 1250,                                                                          Calcd.                                                                            73.24                                                                            4.68                                                                             8.13                                                         1120, 1002                                     159  yellow                                                                             153-155                                                                             (CDCl.sub.3) 3.65(s, 2H), 3.71                                                               (KBr tablet)                                                                         C.sub.22 H.sub.18 N.sub.2 O.sub.3       (24a)                                                                              crystal                                                                            (isopropyl                                                                          (s, 3H), 5.27(bs, 2H), 6.6-                                                                  1737, 1605,                                                                              C  H  N                                       ether)                                                                              8.3(m, 11H)    1473, 1414                                                                           Found                                                                             73.56                                                                            5.41                                                                             7.59                                                         1303, 1230,                                                                          Calcd.                                                                            73.73                                                                            5.06                                                                             7.82                                                         1003, 810,                                                                    714                                            160  yellow                                                                             120-122                                                                             (CDCl.sub.3) 3.25(t, J=6.9Hz, 2H),                                                           (KBr tablet)                                                                         C.sub.23 H.sub.20 N.sub.2 O.sub.3       (28a)                                                                              crystal                                                                            (isopropyl                                                                          3.82(s, 3H), 4.00(t, J=6.9Hz,                                                                1708, 1626,                                                                              C  H  N                                       ether)*                                                                             2H), 4.88(bs, 2H), 6.67-7.90                                                                 1607, 1590,                                                                          Found                                                                             74.20                                                                            5.42                                                                             7.53                                          (m, 10H), 8.24-8.47(m, 2H)                                                                   1479, 1435,                                                                          Calcd.                                                                            74.18                                                                            5.41                                                                             7.52                                                         1258, 1238,                                                                   1130, 1006,                                                                   766                                            161  yellow                                                                             114-115                                                                             (CDCl.sub.3) 2.99(t, J=7.1Hz, 2H),                                                           (KBr tablet)                                                                         C.sub.23 H.sub. 22 N.sub.2 O.sub.3      (29a)                                                                              solid                                                                              (isopropyl                                                                          3.30(s, 3H), 3.83(t, J=7.1Hz,                                                                1712, 1629,                                                                              C  H  N                                       ether)*                                                                             2H), 3.80(s, 3H), 4.88(bs,                                                                   1607, 1487,                                                                          Found                                                                             73.48                                                                            5.99                                                                             7.30                                          2H), 5.72(bs, 1H), 5.90(t,                                                                   1438, 1289,                                                                          Calcd.                                                                            73.78                                                                            5.92                                                                             7.48                                          J=3.2Hz, 1H), 6.36(bs, 1H),                                                                  1265, 1241,                                                    6.63-7.91(m, 6H), 8.29(d,                                                                    1129, 1001,                                                    J=2.4Hz, 1H)   766, 725                                       __________________________________________________________________________

EXAMPLE 16211-[(3-Pyridyl)methyl]imino-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound 25b) EXAMPLE 16311-(3-Pyridyl)imino-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid(Compound 23b) EXAMPLE 16411-(3-Pyridyl)imino-6,11-dihydrodibenz[b,e]oxepin-2-aceticacid·monohydrate (Compound 24b') EXAMPLE 16511-[2-(2-Pyridyl)ethyl]imino-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound 28b) EXAMPLE 16611-[2-(2-Pyridyl)ethyl]imino-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid·0.5 fumarate (Compound 28b') EXAMPLE 16711-[2-(1-Methylpyrrol-2-yl)ethyl]imino-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound 29b)

In Examples 162 through 167, the objective compounds were prepared byhydrolyzing esters of the corresponding oxepine derivatives in a mannersimilar to Example 14 or 15.

Compound 28b' in Example 166 was treated in a manner similar to Example10 to give the product as the fumarate.

Physicochemical properties of the compounds obtained in Examples 162 to167 are shown in Table 5-15.

                                      TABLE 5-15                                  __________________________________________________________________________    Example   MP °C.                                                       No.       (Solvent                                                            (Com-     for                  IR                                             pound                                                                              Appear-                                                                            recrystal-                                                                          NMR            (Method)                                                                             Elemental analysis                      No.) ance lization)                                                                           (Solvent) δ, ppm                                                                       cm.sup.-1                                                                            %                                       __________________________________________________________________________    162  white                                                                              244-245.5                                                                           (DMSO-d.sub.6) 4.5-5.5(m, 4H),                                                               (KBR tablet)                                                                         C.sub.21 H.sub.16 N.sub.2 O.sub.3       (25b)                                                                              solid                                                                              (isopro-                                                                            6.96(d, J=8.6Hz, 1H), 7.37-                                                                  2374, 1701,                                                                              C  H  N                                       panol)                                                                              7.80(m, 6H), 7.87(dd, J=2.2                                                                  1630, 1606,                                                                          Found                                                                             72.96                                                                            4.52                                                                             8.10                                          &8.6Hz, 1H), 8.34(d, J=2.2                                                                   1486, 1428,                                                                          Calcd.                                                                            73.24                                                                            4.68                                                                             8.13                                          Hz, 1H), 8.49(d, J=3.9Hz, 1H),                                                               1312, 1236,                                                    8.57(bs, 1H)   1047, 1005,                                                                   791, 772,                                                                     647                                            163  white                                                                              307-308                                                                             (DMSO-d.sub.6) 5.48(bs, 2H),                                                                 (KBr tablet)                                                                         C.sub.20 H.sub.14 N.sub.2 O.sub.3       (23b)                                                                              solid                                                                              (isopro-                                                                            6.80(d, J=7.8Hz, 1H), 7.04(d,                                                                2368, 1680,                                                                              C  H  N                                       panol)                                                                              J=8.5Hz, 1H), 7.13-7.60(m,                                                                   1662, 1604,                                                                          Found                                                                             72.52                                                                            4.13                                                                             8.50                                          5H), 7.94(dd, J=2.2&8.5Hz,                                                                   1489, 1411,                                                                          Calcd.                                                                            72.72                                                                            4.27                                                                             8.48                                          1H), 8.04(d, J=2.2Hz, 1H),                                                                   1331, 1269,                                                    8.18(d, J=3.2Hz, 1H), 8.63(d,                                                                1185, 1096,                                                    J=2.2Hz, 1H)   1044, 1005,                                                                   775, 767                                       164  white                                                                              230-232                                                                             (DMSO-d.sub.6) 3.60(s, 2H), 5.36                                                             (KBr tablet)                                                                         C.sub.21 H.sub.16 N.sub.3 O.sub.3.H.                                          sub.2 O                                 (24b')                                                                             crystal                                                                            (isopro-                                                                            (s, 2H), 6.75(d, J=7.6Hz, 1H),                                                               1715, 1605,                                                                              C  H  N                                       panol)                                                                              6.89(d, J=8.5Hz, 1H), 7.09-                                                                  1490, 1420,                                                                          Found                                                                             71.70                                                                            4.64                                                                             7.80                                          7.38(m, 5H), 7.56(d, J=7.1Hz,                                                                1300, 1218,                                                                          Calcd.                                                                            71.38                                                                            4.85                                                                             7.92                                          1H), 7.89(d, J=2.2Hz, 1H),                                                                   1015, 815                                                      8.00(bs, 1H), 8.15-8.17(m,                                                    1H)                                                           165  white                                                                              Impossible                                                                          --             --     --                                      (28b)                                                                              amor-                                                                              to measure                                                               phous                                                                              due to                                                                        hygro-                                                                        scopic                                                                        nature                                                              166  white                                                                              unclear                                                                             (DMSO-d.sub. 6) 3.16(bs, 2H), 5.00                                                           (KBr tablet)                                                                         C.sub.22 H.sub.18 N.sub.2 O.sub.3.0.                                          5C.sub.4 H.sub.4 O.sub.4                (28b')                                                                             crystal                                                                            (isopro-                                                                            (s, 2H), 6.58(s, 1H), 6.87                                                                   1699, 1622,                                                                              C  H  N                                       panol)                                                                              (d, J=8.5Hz, 1H), 7.15-7.68                                                                  1606, 1486,                                                                          Found                                                                             63.51                                                                            4.45                                                                             6.70                                          (m, 7H), 7.81(dd, J=2.2&8.5                                                                  1285, 1236,                                                                          Calcd.                                                                            63.45                                                                            4.84                                                                             6.72                                          Hz, 1H), 8.21(d, J=2.2Hz, 1H),                                                               1015, 768,                                                     8.37-8.39(m, 1H)                                                                             655                                            167  white                                                                              unclear                                                                             (DMSO-d.sub.6) 2.96-3.08(m, 3H),                                                             (KBr tablet)                                                                         C.sub.23 H.sub.22 N.sub.2 O.sub.3       (29b)                                                                              crystal                                                                            (isopro-                                                                            3.34(s, 3H), 3.34-3.59(m,                                                                    2904, 1696,                                                                              C  H  N                                       panol)                                                                              2H), 3.6-3.9(m, 2H), 5.03                                                                    1606, 1568,                                                                          Found                                                                             73.23                                                                            5.60                                                                             7.70                                          (bs, 2H), 5.58-5.60(m, 1H),                                                                  1487, 1407,                                                                          Calcd.                                                                            73.32                                                                            5.59                                                                             7.77                                          5.80-5.83(m, 1H), 6.52-6.54                                                                  1315, 1248,                                                    (m, 1H), 6.89(d, J=8.5Hz, 1H),                                                               1201, 1120,                                                    7.40-7.60(m, 4H), 7.82(dd, J=                                                                995, 775,                                                      2.2&8.5Hz, 1H), 8.26(d, J=                                                                   764, 711                                                       2.2Hz, 1H), 12.79(bs, 1H)                                     __________________________________________________________________________

EXAMPLE 168 Methyl11-(3-pyridine)carboxamine-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 30a)

Methyl 11-amino-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compoundo), 4.0 g, obtained in Reference Example 15 was suspended in 200 ml ofmethylene chloride and, 7.0 g of nicotinic chloride and then 50 ml oftriethylamine were added to the suspension. The mixture was stirred atroom temperature for a day. Water was further added to the reactionmixture. After stirring for 2 hours, the reaction mixture was extractedwith 200 ml of methylene chloride. The extract was washed successivelywith saturated sodium bicarbonate aqueous solution and saturated sodiumchloride aqueous solution. After drying over anhydrous magnesiumsulfate, the solvent was distilled off under reduced pressure. Theresulting residue was subjected to silica gel column chromatography(eluting solvent; ethyl acetate:triethylamine=10:1) to give 2.0 g of theproduct.

EXAMPLE 169 Methyl11-(1-imidazolyl)acetamido-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 33a)

Compound o, 10.0 g, was suspended in a solvent mixture of 200 ml ofmethylene chloride and 5.2 ml of triethylamine and, 20 ml of a methylenechloride solution containing 3 ml of chloroacetic chloride was dropwiseadded to the suspension. The mixture was stirred at room temperature forfurther 2 hours. The solvent was distilled off under reduced pressure togive methyl11-chloroacetamide-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate. Thisester was used in the following reaction without further purification.

Crude methyl11-chloroacetamido-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate, 3.0 g,was heated to reflux for 4 hours in 100 ml of toluene together with 0.9g of imidazole. After allowing to cool, the solvent was distilled offunder reduced pressure. The obtained residue was extracted with 300 mlof methylene chloride. The extract was washed successively withsaturated sodium bicarbonate aqueous solution and saturated sodiumchloride aqueous solution. After drying over anhydrous sodium sulfate,the solvent was distilled off under reduced pressure. The resultingresidue was subjected to silica gel column chromatography (elutingsolvent; chlororform:methanol=10:1) to give 1.6 g of the product.

EXAMPLE 170 Sodium11-(3-pyridine)carboxamido-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate.multidot.trihydrate(Compound 30b') EXAMPLE 17111(1-Imidazolyl)acetamido-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound 33b)

In Examples 170 and 171, the objective compounds were prepared byhydroyzing esters of the corresponding oxepine derivative in a mannersimilar to Example 14 or 15.

Compound 30b' in Example 170 was treated in a manner similar to Example62 to give the product as the sodium salt.

Physicochemical properties of the compounds obtained in Examples 168 to171 are shown in Table 5-16.

                                      TABLE 5-16                                  __________________________________________________________________________    Example   MP °C.                                                       No.       (Solvent                                                            (Com-     for                  IR                                             pound                                                                              Appear-                                                                            recrystal-                                                                          NMR            (Method)                                                                             Elemental analysis                      No.) ance lization)                                                                           (Solvent) δ, ppm                                                                       cm.sup.-1                                                                            %                                       __________________________________________________________________________    168  pinkish                                                                            225-227                                                                             (CDCL.sub.3 +DMSO-d.sub.6) 3.86(s, 3H),                                                      --     C.sub.22 H.sub.18 N.sub.2 O.sub.4       (30a)                                                                              crystal                                                                            (isopropyl                                                                          5.12&5.91(ABq, J=12.7Hz,  C  H  N                                       ether)*                                                                             2H), 6.39(d, J=6.0Hz, 1H),                                                                          Found                                                                             70.15                                                                            4.75                                                                             7.36                                          6.91(d, J=8.2Hz, 1H), 7.14-                                                                         Calcd.                                                                            70.58                                                                            4.85                                                                             7.48                                          8.31(m, 8H), 8.55-8.69(m,                                                     1H), 9.03-9.13(m, 1H), 9.34                                                   (d, J=6.0Hz, 1H)                                              169  white                                                                              223-224                                                                             (CDCl.sub.3 +DMSO-d.sub.6) 3.80(s, 3H),                                                      (KBr tablet)                                                                         C.sub.21 H.sub.19 N.sub.3 O.sub.4       (33a)                                                                              solid                                                                              (isopropyl                                                                          4.66(s, 2H), 5.11&5.69(ABq,                                                                  3270, 1718,                                                                              C  H  N                                       ether)                                                                              J=13.8Hz, 2H), 6.10(d, J=6.6                                                                 1669, 1611,                                                                          Found                                                                             66.61                                                                            5.27                                                                             10.98                                         Hz, 1H), 6.74-8.01(m, 10H),                                                                  1556, 1435,                                                                          Calcd.                                                                            66.83                                                                            5.07                                                                             11.13                                         9.26(d, J=6.6Hz, 1H)                                                                         1297, 1265,                                                                   1246, 1128,                                                                   998, 766                                       170  white                                                                              240   (DMSO-d.sub.6 +CD.sub.3 OD) 5.18&5.76                                                        --     C.sub.21 H.sub.15 N.sub.2 O.sub.4                                             Na.3H.sub.2 O                           (30b')                                                                             solid                                                                              (dec.)                                                                              (ABq, J=13.3Hz, 2H), 6.42(s,                                                                            C  H  N                                       (water)                                                                             1H), 6.75(d, J=8.3Hz, 1H),                                                                          Found                                                                             57.62                                                                            4.51                                                                             6.52                                          7.31-8.33(m, 8H), 8.69(dd,                                                                          Calcd.                                                                            57.80                                                                            4.85                                                                             6.42                                          J=1.6, 4.8Hz, 1H), 9.07(d,                                                    J=1.6Hz, 1H)                                                  171  white                                                                              248.5-250                                                                           (DMSO-d.sub.6) 5.07&5.11(ABq,                                                                (KBr tablet)                                                                         C.sub.20 H.sub.17 N.sub.3 O.sub.4       (33b)                                                                              solid                                                                              (dec.)                                                                              J=16.7Hz, 2H), 5.23&5.86                                                                     1683, 1610,                                                                              C  H  N                                       (isopro-                                                                            (ABq, J=13.3Hz, 2H), 6.13(d,                                                                 1550, 1494,                                                                          Found                                                                             66.00                                                                            4.85                                                                             11.33                                   panol)                                                                              J=6.8Hz, 1H), 6.94(d, J=8.5                                                                  1384, 1264,                                                                          Calcd.                                                                            66.11                                                                            4.72                                                                             11.58                                         Hz, 1H), 7.32-7.69(m, 6H),                                                                   1215, 1124,                                                    7.78(dd, J=2.2, 8.5Hz, 1H),                                                                  995, 763                                                       8.03(d, J=2.2Hz, 1H), 9.06(s,                                                 1H), 9.72(d, J=6.8Hz, 1H)                                     __________________________________________________________________________

EXAMPLE 172 Methyl(E)-11-[2-(3-oxo-1-indazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-125a)

Methyl(E)-11-(2-chloroethylidene)-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound h), 2.0 g, obtained in Reference Example 8, 4.3 g of3-indazolinone and 14 ml of Triton B were heated to reflux in 100 ml ofdioxane for 5 hours. After allowing to cool, the solvent was distilledoff under reduced pressure. The obtained residue was extracted with 200ml of ethyl acetate. The extract was washed successively with saturatedsodium bicarbonate aqueous solution and saturated sodium chlorideaqueous solution. After drying over anhydrous magnesium sulfate, thesolvent was distilled off under reduced pressure. The resulting residuewas subjected to silica gel column chromatography (eluting solvent;hexane:ethyl aceate:triethylamine=50:10:1) to give 0.5 g of the product.

EXAMPLE 173 Methyl(E)-11-[2-[(2H-1,4-benzothiazin-3-(4H)-om)-4-yl]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-163a)

In 20 ml of N,N-dimethylformamide, 2.6 go of2H-1,4-benzothiazin-3(4H)-one was stirred at room temperature for 2hours, together with 0.6 g of sodium hydride (6% oily). Then 1.0 g ofCompound h was added thereto followed by further stirring at roomtemperature overnight. The reaction mixture was extracted with 200 ml ofethyl acetate. The extract was washed successively with 1 N hydrochloricacid aqueous solution, saturated sodium bicarbonate aqueous solution andsaturated sodium chloride aqueous solution. After drying over anhydroussodium sulfate, the solvent was distilled off under reduced pressure.The resulting residue was subjected to silica gel column chromatography(eluting solvent; toluene:ethyl acetate=5:1) to give 0.8 g of the crudeproduct.

EXAMPLE 174 Methyl(E)-11-[2-(1,1,3-triozo-2,3-dihydro-1,2-benzisothiazol-2-yl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-164a)

The product was prepared in the same way as in Example 173 except thatsaccharin was used in place of 2H-1,4-benzothiazin-3(4H)-one.

EXAMPLE 175 Methyl(E)-11-[2(2-hydroxy-1-benzimidazolyl)ethylidene[-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-115a)

Compound h, 2.0 g and 4.3 g of 2-hydroxybenzimidazole were treated in amanner similar to Example 173 to give 0.3 of the objective compound.

EXAMPLE 176 Methyl(E)-11-[2-(3-indolyl)]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-122a)

In 40 ml of tetrahydrofuran was dissolved 1.1 g of indole. Under icecooling, 9.5 ml of 1 N ethyl magnesium bromide was dropwise added to thesolution. The mixture was stirred at room temperature for further 2hours. Then, 30 ml of a tetrahydrofuran solution containing 2. 0 g ofCompound h was dropwise added to the reaction mixture under ice cooling.After stirring at room temperature for 2 hours, 10 ml of ammoniumchloride aqueous solution was added to the mixture followed by stirringfor 30 minutes. The reaction mixture was extracted with 300 ml of ethylacetate. The extract was washed successively with saturated sodiumbicarbonate aqueous solution and saturated sodium chloride aqueoussolution. After drying over anhydrous magnesium sulfate, the solvent waddistilled off under reduced pressure. The resulting residue wassubjected to silica gel column chromatography (eluting solvent; hexane:ethyl acetate:triethylamine=50:10:1) to give 0.7 g of the product.

EXAMPLE 177 Methyl(E)-11-[2-(3-pyridyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-36b)

To 50 ml of pyridine was added to 2.0 g of lithium aluminum hydride, andthe mixture was stirred at room temperature for one night. Then, 90 mlof tetrahydrofuran solution containing 5.0 g of Compound h was dropwiseadded thereto under ice-cooling. The mixture was stirred at roomtemperature for 5 hours, and the solvent was distilled off under reducedpressure. The residue was washed with tetrahydrofuran, and the washingswere concentrated under reduced pressure. The residue was subjected tosilica gel column chromatography (eluting solvent; hexane:ethylacetate:triethylamine=10:10:1) to give 1.7 g of the desired product.

Physicochemical properties of the compounds obtained in examples 172 to177 are shown in Table 5-17.

                                      TABLE 5-17                                  __________________________________________________________________________    Example   MP °C.                                                       No.       (Solvent                                                            (Com-     for                 IR                                              pound                                                                              Appear-                                                                            recrystal-                                                                         NMR            (Method)                                                                             Elemental analysis                       No.) ance lization)                                                                          (Solvent) δ, ppm                                                                       cm.sup.-1                                                                            %                                        __________________________________________________________________________    172  yellow                                                                             --   (CDCl.sub.3) 3.89(s, 3H), 5.01                                                               (neat) --                                       (E-125a)                                                                           oil       (d, J=6.8Hz, 2H), 5.0-5.5(b,                                                                 1718, 1499,                                                    2H), 6.53(t, J=6.8Hz, 1H),                                                                   1255, 1122,                                                    6.80(d, J=8.8Hz, 1H), 7.0-                                                                   1010                                                           7.9(m, 9H), 8.11(d, J=2.2Hz,                                                  1H), 8.79(bs, 1H)                                              173  pale --   (CDCl.sub.3) 3.36(s, 2H), 3.84(s,                                                            (neat) --                                       (E-163a)                                                                           yellow    3H), 4.56-5.35(m, 4H), 6.03                                                                  3024, 2948,                                          oil       (t, J=5.9Hz, 1H), 6.40-8.09                                                                  1714, 1669,                                                    (m, 11H)       1605, 1374,                                                                   1246, 1117,                                                                   1005, 767,                                                                    730                                             174  color-                                                                             --   (CDCl.sub.3) 3.87(s, 3H), 4.55                                                               --     [MS(m/z): 461(M.sup.+)]                  (E-164a)                                                                           less      (bs, 2H), 4.5-5.8(b, 2H),                                           amor-     6.21(t, J=7.1Hz, 1H), 6.79(d,                                       phous     J=8.8Hz, 1H), 7.2-8.1(m, 9H),                                                 8.01(d, J=2.2Hz, 1H)                                           175  pale --   (CDCl.sub.3) 3.77(s, 3H), 4.32-                                                              --     --                                       (E-115a)                                                                           yellow    5.60(m, 4H), 6.15(t, J=7.4Hz,                                       oil       1H), 6.30-8.10(m, 12H)                                         176  color-                                                                             --   (CDCl.sub.3) 3.63(d, J=7.90Hz, 1H),                                                          (KBr tablet)                                                                         --                                       (E-122a)                                                                           less      3.87(s, 3H), 4.6-5.8(b, 2H),                                                                 3372, 2966,                                          amor-     6.40(t, J=7.6Hz, 1H), 6.77(d,                                                                1701, 1605,                                          phous     J=8.6Hz, 1H), 7.01-7.49(m,                                                                   1487, 1242,                                                    9H), 7.77(dd, J=2.0&8.6Hz,                                                                   1118, 1003,                                                    1H), 8.05(d, J=2.0Hz, 1H)                                                                    767, 740                                        177  yellow                                                                             --   (CDCl.sub.3) 3.53(d, J=7.5Hz, 2H),                                                           (neat) [MS(m/z): 357(M.sup.+)]                  (E-36a)                                                                            oil       3.87(s, 3H), 6.24(t, J=7.5Hz,                                                                1711, 1606,                                                    1H), 6.78(d, J=8.6Hz, 1H),                                                                   1244, 1117,                                                    7.79(dd, J=2.2&8.6Hz, 1H),                                                                   1003                                                           8.01(d, J=2.2Hz, 1H)                                           __________________________________________________________________________

EXAMPLE 178(E)-11-[2-(3-Oxo-1-indazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid·0.25 hydrate (Compound E-125b') EXAMPLE 179(E)-11-[2-[(2H-1,4-Benzothiazin-3(4H)-on)-4-yl]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound E-163b) EXAMPLE 180(E)-11-[2-(1,1,3-Trioxo-2,3-dihydro-1,2-benzisothiazol-2-yl]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid·0.8 isopropylether·monohydrate (Compound E-164b') EXAMPLE 181(E)-11-[2-[(2-Hydroxy-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound E-115b) EXAMPLE 182(E)-11-[2-(3-Indolyl)]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid 0.2 hydrate (Compound E-122b') EXAMPLE 183(E)-11-[2-(3-Pyridyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid·0.4 isopropanol (Compound E-36b')

In Examples 178 through 183, the objective compounds were prepared byhydrolyzing esters of the corresponding oxepine derivatives in a mannersimilar to Example 14 or 15.

Physicochemical properties of the compounds obtained in Examples 178 to183 are shown in Table 5-18.

                                      TABLE 5-18                                  __________________________________________________________________________    Example   MP °C.                                                       No.       (Solvent                                                            (Com-     for                  IR                                             pound                                                                              Appear-                                                                            recrystal-                                                                          NMR            (Method)                                                                             Elemental analysis                      No.) ance lization)                                                                           (Solvent) δ, ppm                                                                       cm.sup.-1                                                                            %                                       __________________________________________________________________________    178  white                                                                              205-207                                                                             (DMSO-d.sub.6) 4.94(bs, 2H), 6.46                                                            (KBr tablet)                                                                         C.sub.24 H.sub.18 N.sub.2 O.sub.4.0.                                          25H.sub.2 O                             (E-125b')                                                                          crystal                                                                            (dec.)                                                                              (t, J=6.6Hz, 1H), 6.86(d, J=                                                                 1692, 1625,                                                                              C  H  N                                       (isopro-                                                                            8.5Hz, 1H), 6.98-7.04(m, 1H),                                                                1605, 1521,                                                                          Found                                                                             71.46                                                                            4.51                                                                             6.78                                    panol)                                                                              7.29-7.62(m, 7H), 7.75(dd,                                                                   1364, 1311,                                                                          Calcd.                                                                            71.54                                                                            4.63                                                                             6.95                                          J=2.2, 8.5Hz, 1H), 7.97(d,                                                                   1242, 1162,                                                    J=2.2Hz, 1H), 11.90(bs, 1H),                                                                 1004, 763,                                                     12.7(bs, 1H),  742                                            179  yellow                                                                             213-216                                                                             (DMSO-d.sub.6) 3.49(s, 2H), 4.1-                                                             (KBr tablet)                                                                         C.sub.26 H.sub.21 NO.sub.4 S            (E-163b)                                                                           powder                                                                             (isopropyl                                                                          4.5(m, 4H), 5.95(t, J=6.5Hz,                                                                 2926, 1660,                                                                              C  H   N                                      ether)                                                                              1H), 6.71(d, J=8.2Hz, 1H),                                                                   1601, 1374,                                                                          Found                                                                             68.24                                                                            4.40                                                                             3.20                                          6.78(d, J=8.5Hz, 1H), 6.97-                                                                  1262, 1250,                                                                          Calcd.                                                                            69.91                                                                            4.46                                                                             3.26                                          7.60(m, 7H), 7.70(dd, J=2.2,                                                                 1001, 771,                                                     8.5Hz, 1H), 7.87(d, J=2.2Hz,                                                                 744                                                            1H)                                                           180  white                                                                              150   (DMSO-d.sub.6) 4.95&5.38(each                                                                (KBr tablet)                                                                         C.sub.24 H.sub.17 NO.sub.6 S.0.8C.su                                          b.6 H.sub.14 O.H.sub.2 O                (E-164b')                                                                          solid                                                                              (dec.)                                                                              bs, 2H), 5.95(t, J=7.0Hz, 1H),                                                               1680, 1603,                                                                              C  H  N                                       (isopropyl                                                                          6.80(d, J=8.5Hz, 1H), 7.17-                                                                  1313, 1250,                                                                          Found                                                                             63.16                                                                            5.55                                                                             2.50                                    ether)*                                                                             7.72(m, 9H), 7.77(d, J=2.2Hz,                                                                1160, 9997                                                                           Calcd.                                                                            63.21                                                                            5.56                                                                             2.56                                          1H)                                                           181  white                                                                              293-295                                                                             (DMSO-d.sub.6) 4.2-5.6(m, 4H),                                                               (KBr tablet)                                                                         C.sub.24 H.sub.18 N.sub.2 O.sub.4       (E-115b)                                                                           solid                                                                              (methanol)                                                                          6.06(t, J=6.6Hz, 1H), 6.67-                                                                  1698, 1644,                                                                              C  H  N                                             6.69(m, 1H), 6.81(d, J=8.5Hz,                                                                1605, 1487,                                                                          Found                                                                             72.29                                                                            4.43                                                                             6.84                                          1H), 6.91-6.97(m, 3H), 7.44-                                                                 1406, 1373,                                                                          Calcd.                                                                            72.35                                                                            4.55                                                                             7.03                                          7.60(m, 4H), 7.71(dd, J=2.2,                                                                 1310, 1245,                                                    8.5Hz, 1H), 7.89(d, J=2.2Hz,                                                                 1002                                                           1H), 10.78(bs, 1H)                                            182  white                                                                              230-232                                                                             (DMSO-d.sub.6) 3.56(bs, 2H), 5.05                                                            (KBr tablet)                                                                         C.sub.25 H.sub.19 NO.sub.3.0.2H.sub.                                          2 O                                     (E-122b')                                                                          solid                                                                              (aceto-                                                                             &5.55(each bs, 2H), 6.32(t,                                                                  1684, 1605,                                                                              C  H  N                                       nitrile)                                                                            J=7.8Hz, 1H), 6.82(d, J=8.5                                                                  1406, 1316,                                                                          Found                                                                             78.15                                                                            5.04                                                                             3.39                                          Hz, 1H), 6.94-7.59(m, 8H),                                                                   1247, 1000,                                                                          Calcd.                                                                            77.99                                                                            5.08                                                                             3.64                                          7.19(d, J=2.2Hz, 1H), 7.70                                                                   769, 741,                                                      (dd, J=2.2, 8.5Hz, 1H), 7.92                                                  (d, J=2.2Hz, 1H), 10.88(bs,                                                   1H), 12.65(bs, 1H)                                            183  white                                                                              252-255                                                                             (DMSO-d.sub.6) 3.51(bs, 2H), 5.05                                                            (KBr tablet)                                                                         C.sub.22 H.sub.17 NO.sub.3.0.8C.sub.                                          3 H.sub.8 O                             (E-36b')                                                                           crystal                                                                            (dec.)                                                                              &5.53(each bs, 2H), 6.26(t,                                                                  1702, 1606,                                                                              C  H  N                                       (isopro-                                                                            J=7.6Hz, 1H), 6.82(d, J=8.6                                                                  1487, 1428,                                                                          Found                                                                             75.98                                                                            5.42                                                                             3.52                                    panol)                                                                              Hz, 1H), 7.31-7.65(m, 6H),                                                                   1242, 1126,                                                                          Calcd.                                                                            75.84                                                                            5.54                                                                             3.81                                          7.71(dd, J=2.2&8.5Hz, 1H),                                                                   1000                                                           7.91(d, J=2.2Hz, 1H), 8.41                                                    (bs, 2H)                                                      __________________________________________________________________________

The structures of intermediates obtained in Reference Exampleshereinafter are illustrated in Table 6.

                                      TABLE 6                                     __________________________________________________________________________     ##STR228##                                                                   Compound                                                                      (Reference Example)                                                                      X.sup.1X.sup.2                                                                       G.sup.o                                                                          R.sup.o    X.sup.o                                       __________________________________________________________________________    a (1)      CH.sub.2 O                                                                           H  2-COOCH.sub.3                                                                           O                                              b (2)      CH.sub.2 O                                                                           H  2-COOCH.sub.3                                                                           OH                                             c (3)      CH.sub.2 O                                                                           H  2-COOC.sub.2 H.sub.5                                                                    OH                                             d (4)      CH.sub.2 O                                                                           H  2-COOn-C.sub.4 H.sub.9                                                                  OH                                             e (5)      CH.sub.2 O                                                                           H  2-CH.sub.2 COOCH.sub.3                                                                  O                                              f (6)      CH.sub.2 O                                                                           H  2-CH.sub.2 COOCH.sub.3                                                                  OH                                             g (7)      CH.sub.2 O                                                                           H  2-C(CH.sub.3).sub.2 COOCH.sub.3                                                         OH                                             h (8)      CH.sub.2 O                                                                           H  2-COOCH.sub.3                                                                           CHCH.sub.2 Cl                                  i (9)      CH.sub.2 O                                                                           H  3-COOCH.sub.3                                                                           CHCH.sub.2 Cl                                  j (10)     CH.sub.2 O                                                                           H  9-COOCH.sub.3                                                                           CHCH.sub.2 Cl                                  k (11)     CH.sub.2 O                                                                           9-Br                                                                             2-COOCH.sub.3                                                                           CHCH.sub.2 Cl                                  l (12)     CH.sub.2 O                                                                           H  2-CH.sub.2 COOCH.sub.3                                                                  CHCH.sub.2 Cl                                  m (13)     CH.sub.2 O                                                                           H  2-CH.sub.2 COOCH.sub.3                                                                  CHCH.sub.2 CH.sub.2 OSO.sub.2 CH.sub.3         n (14)     CH.sub.2 O                                                                           H  2-CH.sub.2 COOCH.sub.3                                                                  SCH.sub.2 CH.sub.2 I                           o (15)     CH.sub.2 O                                                                           H  2-CH.sub.2 COOCH.sub.3                                                                  NH.sub.2                                       p (16)     CH.sub.2 O                                                                           H  3-COOCH.sub.3                                                                           OCH.sub.3                                      q (17)     CH.sub.2 S                                                                           H  2-COOCH.sub.3                                                                           OCH.sub.3                                      r (18)     CH.sub.2 CH.sub.2                                                                    H  2-COOCH.sub.3                                                                           CHCH.sub.2 Cl                                  s (19)     CH.sub.2 CH.sub.2                                                                    H                                                                                 ##STR229##                                                                             CH.sub.2 CH.sub.2 OH                           t (20)     CHCH   H  2-COOCH.sub.3                                                                           CHCH.sub.2 Cl                                  u (21)     CHCH   H  2-CH.sub.2 COOCH.sub.3                                                                  CHCH.sub.2 Cl                                  v (22)     CHCH   H                                                                                 ##STR230##                                                                             CH.sub.2 CH.sub.2 OH                           __________________________________________________________________________

REFERENCE EXAMPLE 1 Methyl11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound a)

A mixture of 348.9 g of methyl p-hydroxybenzoate sodium salt, 402.4 g ofphthalide and 200 g of sodium chloride was stirred at 150° C. for 6hours. After completion of the reaction, the reaction mixture was cooledto room temperature and 4 liters of 10% acetic acid aqueous solutionwere added thereto. The mixture was allowed to stand at room temperatureovernight. After stirring at room temperature for 3 hours, crystals weretaken by filtration. To the crystals was added 6 liters of water. Afterstirring at room temperature for 30 minutes, the crystals were taken outby filtration. To the crystals was added 3 liters of toluene. Themixture was stirred at room temperature for an hour. The crystals weretaken out by filtration and dried by heating under reduced pressure togive 393.9 g of 2-(4-methoxycarbonylphenoxy)methyl benzoate.

IR (KBR table, cm⁻¹): 3400, 1700, 1610, 1260, 1235

In 5.0 liters of methylene chloride was suspended 392.7 g of the thusobtained phenoxy compound and, 266.0 g of trifluoroacetic anhydride wasadded to the suspension. After stirring at room temperature for an hour,19.4 g of boron trifluoride ethyl ether complex was added to the mixturefollowed by stirring at room temperature of 2 hours. The reactionsolution was poured into ice water. After fractionation, the organicphase was washed with a diluted sodium hydroxide aqueous solution andthen with water and dried over anhydrous magnesium sulfate.Concentration under reduced pressure gave 335.3 g of the product aswhite crystals (recrystallized from isopropyl ether).

Melting point: 128°-129° C.

    ______________________________________                                        Elemental analysis: as C.sub.16 H.sub.12 O.sub.4                                              C    H                                                        ______________________________________                                        Found (%)         71.55  4.48                                                 Calcd. (%)        71.63  4.51                                                 ______________________________________                                    

NMR (CDCl₃, δ, ppm): 3.84(s, 3H), 5.14(s, 2H), 6.87-8.93(m, 7H)

IR (KBr tablet, cm⁻¹): 1710, 1650, 1610, 1250, 1010

REFERENCE EXAMPLE 2 Methyl11-hydroxy-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound b)

Compound a, 50 g, obtained in Reference Example 1 was suspended in 300ml of methanol and 6.3 g sodium bororhydride was added to thesuspension. The mixture was stirred at room temperature for 2 hours.After completion of the reaction, 10 ml of acetic acid and 300 ml ofwater were added thereto followed by stirring for 30 minutes. Insolublematters were taken out by filtration and washed with methanol and thenwith water. By drying with heating under reduced pressure, 40 g of theproduct was obtained.

NMR (CDCl₃ δ, ppm): 2.16(s, 6H), 2.30-2.76(m, 4H), 3.83.(s, 3H), 4.83and 6.40(ABq, J=12.6Hz, 2H), 5.01(s, 1H),6.79-7.93(m, 7H)

IR (neat, cm⁻¹): 2950, 1710, 1240, 1015

REFERENCE EXAMPLE 3 Ethyl11-hydroxy-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound c)

The corresponding starting material was used and treated in a mannersimilar to Reference Examples 1 and 2 to give the product as colorlessoil.

NMR (CDCl₃, δ, ppm): 1.31(t, J=7Hz, 3H), 3.60(d, J=3Hz, 1H), 4.25(q,J=7Hz, 2H), 4.91 and 5.95(ABq, J=12.5Hz, 2H), 5.61(d, J=3Hz, 1H),6.69-8.12(m, 7H)

IR (neat, cm⁻¹): 3430, 1675, 1610, 1480, 1250

REFERENCE EXAMPLE 4 n-Butyl11-hydroxy-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound d)

The corresponding starting material was used and treated in a mannersimilar to Reference Examples 1 and 2 to give the product as whitecrystals (recrystallized from isopropyl ether).

Melting point: 108°-110° C.

NMR (CDCl₃, δ, ppm): 0.7-2.0(m, 7H), 3.21(bs, 1H), 4.23(t, J=6.3Hz, 2H),4.94 and 5.98(ABq, J=12.7Hz, 2H), 5.62(s, 1H), 6.79(d, J=8.4Hz, 1H),7.2-7.4 (m, 4H), 7.77(dd, J=2.3, 8.4Hz, 1H), 7.99(d, J=2.3Hz, 1H)

REFERENCE EXAMPLE 5 Methyl11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetate (Compound e)

The corresponding starting material was treated in a manner similar toReference Example 1 to give the product as pale yellow crystals(recrystallized from methanol).

Melting point: 75°-76° C.

REFERENCE EXAMPLE 6 Methyl11-hydroxy-6,11-dihydrodibenz[b,e]oxepin-2-acetate (Compound f)

The compound e obtained in Reference Example 5 was treated in a mannersimilar to Reference Example 2 to give the product as pale yellowcrystals (recrystallized from diethyl ether).

Melting point: 85°-87°0 C.

NMR (CDCl₃, δ, ppm): 2.08(s, 3H), 3.49(s, 2H), 3.59(s, 3H), 4.89 and5.75(ABq, J=13Hz, 2H), 5.54(bs, 1H), 6.7-7.4(m, 7H)

REFERENCE EXAMPLE 7 Methyl2-(11-hydroxy-6,11-dihydrodibenz[b,e]oxepin)-2-yl)-2-methylpropionate(Compound g)

The corresponding starting material was treated in a manner similar toReference Examples 1 and 2 to give the product as colorless oil.

NMR (CDCl₃, δ, ppm): 1.56(s, 6H), 3.62(s, 3H), 4.97 and 5.90(ABq,J=13.1Hz, 2H), 5.61(s, 1H), 6.87(d, J=8.3Hz, 1H), 7.05-7.40(m, 6H)

IR (neat, cm⁻¹): 3418, 1708, 1610, 1231, 1012

REFERENCE EXAMPLE 8 Methyl(E)-11-(2-chloroetylidene-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound h)

1-Methylpiperazine, 30 ml, and 74 g of paraformaldehyde were dissolvedin 2 l of tetrachloroethane and 100 ml of trifluoroacetic acid wasdropwise added to the solution. After stirring at 60° C. for 2 hours, asolution of 36 g of methyl1-methylene-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate in 600 ml oftetrachloroethane was dropwise added to the reaction mixture followed bystirring at 90° C. for further 3 hours. The reaction mixture wasconcentrated to dryness under reduced pressure and 4 N hydrochloric acidaqueous solution was added to the residue to adjust pH to 1. Then, themixture was washed with diethyl ether. Thereafter, 10 N sodium hydroxideaqueous solution was added to adjust pH to 13. Extraction was performedwith 3 l of methylene chloride. After washing with saturated sodiumchloride aqueous solution and drying over anhydrous sodium sulfate, thesolvent was distilled off under reduced pressure. The resulting residuewas subjected to silica gel column chromatography (eluting solvent;hexane: ethyl acetate: triethylamine=5:5:1) to give 44 g of colorlesoily methyl11-[2-(4-methyl-1-piperazinyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate.

MS (m/z): 378 (M⁺)

NMR (CDCl₃, δ, ppm): 2.24(S, 3H), 2.45(x, 8H), 2.94-3.32(m, 2H), 3.84(s,3H), 5.22(bs, 2H), 5.85 and 6.22(t, J=6.8Hz, 1H), 6.66-8.07(m, 7H)

E-form compound, 21.5 g, isolated from the Z/E mixture described aboveaccording to the conventional manner and 23.5 go of sodium acetate weresuspended in 250 ml of dichloroethane and, 27.1 ml of ethylchloroformate was dropwise added tot eh suspension. After completion ofthe dropwise addition, the mixture was stirred at room temperature foran hour and the solvent was distilled off under reduced pressure. Theresidue was extracted with 400 ml of ethyl acetate. After washing withsaturated sodium chloride aqueous solution and drying over anhydroussodium sulfate, the solvent was distilled off under reduced pressure.The obtained crude product was recrystallized firm isopropanol to give14.3 go of the product as white crystals.

Melting point: 134°-135° C.

    ______________________________________                                        Elemental analysis: as C.sub.18 H.sub.15 ClO.sub.3                                            C    H                                                        ______________________________________                                        Found (%)         68.55  4.77                                                 Calcd. (%)        68.68  4.80                                                 ______________________________________                                    

NMR (CDCl₃, δ, ppm): 3.90(s, 3H), 4.16(d, J=8.1Hz, 2H), 4.88(bs, 1H),5.57(bs, 1H), 6.31(t, J=8.1Hz, 1H), 6.79-8.04(m, 7H)

REFERENCE EXAMPLE 9 Methyl(E)-11-(2-chloroethylidene)-6,11-dihydrodibenz[b,e]oxepin-3-carboxylate(Compound i)

The corresponding starting material was treated in a manner similar toReference Example 8 to give the product as white crystals.

Melting point: 102°-104° C.

    ______________________________________                                        Elemental analysis: as C.sub.18 H.sub.15 ClO.sub.3                                            C    H                                                        ______________________________________                                        Found (%)         68.50  4.71                                                 Calcd. (%)        68.68  4.80                                                 ______________________________________                                    

NMR (CDCl₃, δ, ppm): 3.87(s, 3H), 4.14(d, J=8.0Hz, 2H), 5.22(bs, 2H),6.29(t, J=8.0Hz, 1H), 7.26-7.61(M, 7H)

IR (KBr tables, cm⁻¹): 1718, 1558, 1293, 1235, 1095, 1028

REFERENCE EXAMPLE 10 Methyl(E)-11-(2-chloroethylidene)-6,11-dihydrodibenz[b,e]oxepin-9-carboxylate(Compound j)

The corresponding starting material was treated in a manner similar toReference Example 8 to give the product as white solid.

Melting point: 83°-85° C.

    ______________________________________                                        Elemental analysis: as C.sub.18 H.sub.15 ClO.sub.3                                            C    H                                                        ______________________________________                                        Found (%)         68.49  4.81                                                 Calcd. (%)        68.68  4.80                                                 ______________________________________                                    

NMR (CDCl₃ δ, ppm): 3.92(s, 2H), 4.12(d, J=8.1 Hz, 2H, 5.21(bs, 2H),6.27(t, J=8.1Hz, 1H), 6.7-8.1(m, 7H)

IR (KBR tablet, cm⁻¹): 1696, 1290, 1262, 1222, 1101 1008

REFERENCE EXAMPLE 11 Methyl9-bromo-11-(2-chloroethylidene)-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound k)

The corresponding starting material was treated in a manner similar toReference Example 8 to give the product as pale yellow oil.

NMR (CDCl₃, δ, ppm): 3.88(s, 3H), 4.13(d, J=7.5Hz, 2H), 4.7-5.6(m, 2H),6.36(t, J=7.5Hz, 1H), 6.8-8.2(m, 6H)

REFERENCE EXAMPLE 12 Methyl(E)-11-(2-chloroethylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetate(Compound l)

The corresponding starting material was treated in a manner similar toReference Example 8 to give the product as white crystals(recrystallized from isopropanol).

Melting point: 172°-128° C.

    ______________________________________                                        Elemental analysis: as C.sub.19 H.sub.17 ClO.sub.3                                            C    H                                                        ______________________________________                                        Found (%)         69.21  5.35                                                 Calcd. (%)        69.41  5.21                                                 ______________________________________                                    

NMR (CDCl₃ δ, ppm): 3.55(s, 2H), 3.69(s, 3H), 4.14(d, J=8.1Hz, 2H),4.7-5.4(m, 2H), 6.23(t, J-=8.1Hz, 1), 6.74(d, J=8.1Hz, 1H), 6.95-7.40(m,6H)

IR (KBr tablet, cm⁻¹): 1734, 1489, 1284, 1257, 1227, 1138, 1004

REFERENCE EXAMPLE 13 Methyl(Z,E)-11-[3-(methylsulfonyl)oxy]propylidene-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound m)

[3-[(Tetrahydro-2H-pyran-2-yl)oxy]propyl]triphenylphosphonium bromide,40.0 g, was suspended in 250 ml of tetrahydrofuran. Under ice cooling innitrogen atmosphere, 50 ml of n-butyl lithium/hexane solution (1.6 N)was dropwise added to the suspension. After stirring at room temperaturefor further an hour, 15.0 g of Compound a obtained in Reference Example1 was added thereto followed by stirring at room temperature for 12hours. After 50 ml of water was added to the reaction mixture, it wasextracted with 1 l of ethyl acetate. After washing thrice with saturatedsodium chloride aqueous solution and drying over anhydrous sodiumsulfate, the solvent was distilled off under reduced pressure. Theobtained residue was dissolved in 500 ml of dioxane and 200 ml of waterand 1.0 g of p-toluenesulfonic acid were added to the solution followedby heating to reflux for an hour. The mixture was concentrated underreduced pressure. The obtained residue was extracted with 1 l of ethylacetate. After washing successively with saturated sodium bicarbonateaqueous solution and saturated sodium chloride aqueous solution, theextract was dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure. The resulting residue wassubjected to silica gel column chromatography (eluting solvent;toluene:ethyl acetate=1:1) to give 9.8 g of methyl(Z,E)-11-(3-hydroxy)propylidene-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate.

NMR (CDCl₃ δ, ppm): 2.17-2.72(m, 2H), 3.37-3.76(m, 2H), 3.77(s, 3H),4.68-5.43(m, 1H), 5.70(t, J=7.4Hz, 0.9H; Z-form), 6.40(t, J=6.9Hz, 2.1H;E-form), 6.52-8.12(m, 7H)

The thus obtained hydroxy product, 3.5 g, was dissolved in 50 ml ofpyridine and 1.7 ml of methanesulfonyl chloride was dropwise added underice cooling. After stirring for further an hour under ice cooling, thesolvent was distilled off under reduced pressure. The residue wasextracted with 200 ml of ethyl acetate. The extract was washed insuccession with 1 N hydrochloric acid aqueous solution, saturated sodiumbicarbonate aqueous solution and saturated sodium chloride aqueoussolution. After drying over anhydrous sodium sulfate, the solvent wasdistilled off under reduced pressure to give 4.3 g of the produce(Z/E=7/3) as colorless oil.

NRM (CDCl₃, δ, ppm): 2.5-3.0(m, 2H), 3.00(s, 3H), 3.86(s, 3H), 4.17(t,J=6.3Hz, 2H), 5.26(bs, 1H), 5.74 and 6.09(each t, J=7.5Hz, 1H),6.7-8.1(m, 7H)

REFERENCE EXAMPLE 14 Methyl11-(2-iodoethyl)thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound n)

In 400 ml of methylene chloride was suspended 40.0 g of Compound bobtained in Reference Example 2. Trifluoroacetic anhydride, 21.0 ml, wasadded to the suspension followed by stirring at room temperature for anhour. Them, 10.7 ml of 2-mercaptoethanol was added to the mixturefollowed by stirring for further 4 hours. After 100 ml of methylenechloride was added to the reaction mixture, the mixture was washed withsaturated aqueous sodium chloride solution. After drying over anhydrousmagnesium sulfate, the solvent was distilled off under reduced pressure.The obtained crude product was recrystallized from toluene to give 37.6g of methyl11-(2-hydroxyethyl)thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate aswhite crystals.

Melting point: 128°-130° C.

    ______________________________________                                        Elemental analysis: as C.sub.18 H.sub.18 O.sub.4 S                                            C    H                                                        ______________________________________                                        Found (%)         65.26  5.55                                                 Calcd. (%)        65.43  5.49                                                 ______________________________________                                    

NMR (CDCl₃, δ, ppm): 2.66(dt, J=2.1, 6.0Hz, 2H), 3.69(t, J=5.9Hz, 2H),3.89(s, 3H), 4.91 and 6.43(ABq, J=12.7Hz, 2H), 5.09(s, 1H), 6.82-7.98(m,7H)

IR (KBr tablet, cm⁻¹): 3420, 1708, 1683, 1610, 1437, 1318, 1008

The thus obtained hydroxyethyl compound, 20.0 g, was dissolved in 200 mlof dimethylformamide, and 12 ml of 2,4,6-cholidine and 4.0 g of lithiumchloride were added to the solution. Under ice cooling, 5.4 ml ofmethanesulfonyl chloride was dropwise added to the mixture. Afterstirring at room temperature overnight, the solvent was distilled offunder reduced pressure. The residue was extracted with ethyl acetate.The extract was washed, in succession, with 1 N hydrochloric acidaqueous solution and then with saturated aqueous sodium chloridesolution. After drying over anhydrous magnesium sulfate, the solvent wasdistilled off under reduced pressure. The obtained residue was subjectedto silica gel column chromatography (eluting solvent; hexane: ethylacetate=5:1) and further crystallized from hexane to give 20.8 g ofmethyl1-(2-chloroethyl)thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate.

Melting point: 100°-102 C.

    ______________________________________                                        Elemental analysis: as C.sub.18 H.sub.17 ClO.sub.3 S                                          C    H                                                        ______________________________________                                        Found (%)         61.77  4.80                                                 Calcd. (%)        61.97  4.91                                                 ______________________________________                                    

NMR (CDCl₃, δ, ppm): 2.54-3.62(m, 4H), 3.84(s, 3H), 5.04(s, 1H), 4.87and 6.37(ABq, J=13.2Hz, 2H), 6.76-8.12(m, 7H)

The thus obtained chloroethyl compound, 10.1 g, obtained as above wasdissolved in 150 ml of acetonitrile, and 14.6 g of sodium iodide wasadded to the solution. The mixture was heated to reflux for 5 hours.After allowing to cool, the reaction mixture was extracted with ethylacetate and the extract was washed twice with saturated sodium chlorideaqueous solution. After drying over anhydrous magnesium sulfate, thesolvent was distilled off under reduced pressure. The residue wassubjected to silica gel column chromatography (eluting solvent;hexane:ethyl acetate=10:1) and further solidified with hexane to give3.1 g of the product as white solid.

Melting point: 111 -113° C.

    ______________________________________                                        Elemental analysis: as C.sub.18 H.sub.17 IO.sub.3 S                                           C    H                                                        ______________________________________                                        Found (%)         49.08  3.71                                                 Calcd. (%)        49.10  3.89                                                 ______________________________________                                    

NMR (CDCl₃, δ, ppm): 2.68-3.22(m, 4H), 3.88(s, 3H), 5.09(s, 1H), 4.91and 6.37(ABq, J=13.2Hz, 2H), 6.78-8.08(m, 7H)

REFERENCE EXAMPLE 15 Methyl11-amino-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound o)

The produce was synthesized as white solid in a manner similar to themethod of Example 32 in Japanese Published Unexamined Patent ApplicationNo. 21679/1983.

Melting point: 99°-100° C.

NMR (CDCl₃, δ, ppm): 3.82(s, 3H), 4.95 and 6.21(ABq, J=12.6Hz, 2H),5.14(s, 1H), 6.80(t, J=9.0Hz, 1H), 7.0-7.3(m, 4H), 7.74(dd, J=2.0,9.0Hz, 1H), 7.93(d, J=2.0Hz, 1H)

REFERENCE EXAMPLE 16 Methyl11-methoxy-6,11-dihydrodibenz[b,e]oxepin-3-carboxylate (Compound p)

3-Bromo-11-methoxy-6,11-dihydrodibenz[b,e]oxepine, 30 g, was dissolvedin 500 ml of tetrahydrofuran. After cooling to -78° C., 65 ml of 1.6 Nn-butyl lithium/hexane solution was dropwise added to the solution in anitrogen atmosphere followed by stirring at -78° C. for further 40minutes. The reaction solution was dropwise added onto 100 g of dry ice,which was allowed to stand to elevate to room temperature. The solventwas distilled off under reduced pressure. To the residue obtained, wereadded 500 ml of methanol and 10 ml of conc. sulfuric acid. The mixturewas heated to reflux for 2 hours. After allowing to cool, the solventwas distilled off under reduced pressure. The residue was extracted with500 ml of ethyl acetate. After washing successively with saturatedsodium chloride aqueous solution, saturated sodium bicarbonate aqueoussolution and saturated sodium chloride aqueous solution, the extract wasdried over anhydrous magnesium sulfate. The solvent was the distilledoff under reduced pressure. The residue was subjected to silica gelcolumn chromatography (eluting solvent; hexane: ethyl acetate=1:1) togive 19.3 g of the product as pale yellow oil.

NMR (CDCl₃, δ, ppm): 3.34(s, 3H), 3.86(s, 3H), 4.93 and 5.99(ABq,J=12.4Hz, 2H), 5.07(s, 1H), 7.24-7.62(m, 7H)

REFERENCE EXAMPLE 17 Methyl11-methoxy-6,11-dihydrodibenzo[b,e]thiepin-2-carboxylate (Compound q)

p-Bromothiophenol, 50.0 g, was suspended in 150 ml of methanol and 14.9g of sodium methoxide was added to the suspension followed by stirringat 50° C. for an hour. The solvent was distilled off under reducedpressure and 35.5 g of phthalide was added to the residue followed bystirring at 180° C. for 3 hours. After allowing to cool to roomtemperature, 200 ml of water was added to the reaction mixture. Themixture was dissolved with heating. After allowing to cool, pH wasadjusted to 1.5 with conc. hydrochloric acid. The precipitated crudeproduct was taken by filtration. After drying, the crude product wasfurther recrystallized from toluene to give 56.3 g of2-[(4-bromophenyl)thio]methylbenzoic acid.

Melting point: 139°-140° C.

The aforesaid compound, 12.0 g, was stirred at 90° C. together with120.0 g of polyphosphoric acid. The reaction solution was poured onto 1liter of ice followed by stirring for further an hour. The precipitatedcrude product was taken by filtration. After drying, the crude productwas further recrystallized from toluene to give 9.0 g of2-bromo-11-oxo-6,11-dihydrodibenzo[b,e]thiepin.

Melting point: 151°-152° C.

The aforesaid compound, 20.0 g, was suspended in a solvent mixture of500 ml of methanol and 300 ml of tetrahydrofuran and 4.5 g of sodiumborohydride was added to the suspension followed by stirring at roomtemperature for an hour. The solvent was distilled off under reducedpressure and the residue was recrystallized from methanol to give 12.0 gof 2-bromo-11-hydroxy-6,11-dihydrodibenzo[b,e]thiepine.

Melting point: 169°-170° C.

The aforesaid compound, 8.6 g, was suspended in 180 ml of methanol and0.5 g of p-toluenesulfonic acid was added to the suspension followed byheating to reflux for an hour. The solvent was distilled off underreduced pressure and the residue was extracted with 200 ml of ethylacetate. After washing successively with saturated sodium chlorideaqueous solution and then with saturated sodium bicarbonate aqueoussolution, the extract was dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure. The resulting crudeproduct was recrystallized from hexane to give 7.8 g of2-bromo-11-methoxy-6,11-dihydrodibenzo[b,e]thiepine.

Melting point: 68°-71° C.

The aforesaid compound, 19.0 g, and 8.0 g of cuprous cyanide were heatedto reflux in 100 ml of dimethylformamide for 8 hours. After allowing tocool, 25 ml of ethylenediamine was added thereto. The mixture wasstirred at 60° C. for 30 minutes and 100 ml of water was added theretofollowed by stirring at 60° C. for further 30 minutes. After allowing tocool, the reaction mixture was extracted with 500 ml of ethyl acetate.Insoluble matters were filtered off and washed 3 times with saturatedsodium chloride aqueous solution. After drying over anhydrous sodiumsulfate, the solvent was distilled off under reduced pressure. Theresulting residue was subjected to silica gel column chromatography(eluting solvent; hexane:ethyl acetate=1:1) and further recrystallizedfrom ethanol to give 11.3 g of1-methoxy-2-cyano-6,11-dihydrodibenzo[b,e]thiepine.

Melting point: 117°-118° C.

The aforesaid compound, 7.3 g, was heated to reflux in a solvent mixtureof 300 ml of conc. hydrochloric acid and 200 ml of acetic acid for 8hours. The solvent was distilled off under reduced pressure and 200 mlof methanol and 0.5 g of p-toluenesulfonic acid were added to theobtained residue. The mixture was heated to reflux for 3 hours. Afterallowing to cool, the solvent was distilled off under reduced pressureand the residue was extracted with 500 ml of ethyl acetate. Afterwashing successively with saturated sodium chloride aqueous solution andthen with saturated sodium bicarbonate aqueous solution, the extract wasdried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure. The resulting residue was subjected to silica gelcolumn chromatography (eluting solvent; hexane: ethyl acetate=5:1) togive 4.5 g of the product as pale yellow amorphous.

IR (CHCl₃, cm⁻¹): 2994, 2952, 1715, 1437, 1301, 1120

REFERENCE EXAMPLE 18 Methyl(Z,E)-5-(2-chloroethylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-3-carboxylate(Compound r)

The corresponding starting material was used and treated in a mannersimilar to Reference Example 8 to give the product (Z/E=7/3) as paleyellow oil.

NMR (CDCl₃, δ, ppm): 2.8-3.4(m, 4H), 3.87(s, 2H), 3.89(s, 1H),4.0-4.3(m, 2H), 6.09(t, J=7.6Hz, 0.7H; Z-form), 6.11(t, J=7.6Hz, 0.3H;E-form), 7.0-7.3(m, 5H), 7.7-8.0(m, 2H)

REFERENCE EXAMPLE 195-(2-Hydroxyethyl)-3-(4,4-dimethyl-2)oxazolin-2-yl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene(Compound s)

Sodium hydride, 4.9 g, was added to 100 ml of a solution of 22 ml ofethyl diethylphosphonoacetate in tetrahydrofuran followed by stirring atroom temperature for 15 minutes. Then, 100 ml of 6.8 g of5-oxo-3-(4,4-dimethyl-2-oxazolin-2-yl)-6,11-dihydro-5H-dibenzo[a,d]cycloheptenein tetrahydrofuran was dropwise added to the mixture. The resultingmixture was heated to reflux for an hour. To the reaction solution wasadded 30 ml of ice water followed by extracting with 300 ml of ethylacetate. The extract was successively washed with 1 N hydrochloric acidaqueous solution, saturated sodium bicarbonate aqueous solution. Afterdrying over anhydrous magnesium sulfate, the solvent was distilled offunder reduced pressure. The obtained residue was subjected to silica gelcolumn chromatography (eluting solvent; hexane:ethyl acetate=3:1) togive 2.1 g of(Z,E)-5-(ethoxycarbonylmethylene)-3-(4,4-dimethyl-2-oxazolin-2-yl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepteneas pale yellow oil.

NMR (CDCl₃, δ, ppm): 1.11(t, J=7.0Hz, 2H), 1.38(s, 6H), 2.94-3.36(m,4H), 4.05(q, J=7.0Hz, 2H), 4.09(s, 2H), 6.29(s, 1H), 7.06-7.29(m, 5H),7.75(dd, J=1.8, 7.9Hz, 1H), 7.94(d, J=1.8Hz, 1H)

The thus obtained compound, 1.6 g, was dissolved in 50 ml oftetrahydrofuran and 0.7 g of lithium aluminum hydride was added to thesolution followed by stirring at room temperature for 30 minutes. Then,methanol, water and 1 N hydrochloric acid aqueous solution were dropwiseadded to the mixture in succession. Thereafter, inorganic residue wasfiltered off. To the filtrate was added 200 ml of ethyl acetate. Themixture was washed with saturated aqueous sodium chloride solution.After drying over anhydrous magnesium sulfate, the solvent was distilledoff under reduced pressure to give 0.36 g of the product as pale yellowoil.

NMR (CDCl₃, δ, ppm): 1.35(s, 6H), 2.22-2.45(m, 3H), 2.94-3.58(m, 4H),3.58(t, J=6.4Hz, 2H), 4.06(s, 2H), 4.29(t, J=7.5Hz, 1H), 7.08-7.26(m,5H), 7.65(dd, J=1.5, 7.8Hz, 1H), 7.82(d, J=1.5Hz, 1H)

REFERENCE EXAMPLE 20 Methyl(Z,E)-5-(2-chloroethylidene)-5H-dibenzo[a,d]cycloheptene-3-carboxylate(Compound t)

The corresponding starting material was treated in a manner similar toReference Example 8 to give the product (Z/E=1/1) as pale yellow oil.

NMR (CDCl₃, δ, ppm): 3.92(s, 3H), 4.03(d, J=7.9Hz, 1H), 4.05(d, J=8.1Hz,1H), 5.81(t, J=7.9Hz, 0.5H; Z-form), 5.82(t, J=8.1Hz, 0.5H; E-form),6.90(s, 1H), 6.92(s, 1H), 7.1-7.5(m, 5H), 7.8-8.1(m, 2H)

REFERENCE EXAMPLE 21 Methyl(Z,E)-5-(2-chloroethylidene)-5H-dibenzo[a,d]cycloheptene-3-acetate(Compound u)

The corresponding starting material was treated in a manner similar toReference Example 8 to give the product (Z/E=1/1) as pale yellow oil.

NMR (CDCl₃, δ, ppm): 3.62(s, 2H), 3.64 and 3.65(each s, 3H), 4.00 and4.01 (each d, J=8.1Hz, 2H), 5.75 and 5.76(each t, J=8.1Hz, 1H), 6.80(s,2H), 7.11-7.38(m, 7H)

REFERENCE EXAMPLE 225-(2-Hydroxyethyl)-3-(4,4-dimethyl-2-oxazolin-2-yl)-5H-dibenzo[a,d]cycloheptene(Compound v)

The corresponding starting material was treated in a manner similar toReference Example 19 to give the product as pale yellow oil.

NMR (CDCl₃, δ, ppm): 1.29(s, 6H), 1.82-2.05(m, 2H), 3.29(t, J=6.3Hz,2H), 3.44-3.79(m, 1H), 4.02(s, 2H), 4.29(t, J=.7.7Hz, 1H), 6.82(s, 1H),6.83(s, 1H), 7.00-7.33(m, 5H), 7.27(dd, J=1.6, 8.0Hz, 1H), 7.92(d,J=1.8Hz, 1H)

PHARMACEUTICAL PREPARATION 1 Tablet

A tablet having the following composition is prepared in a conventionalmanner.

    ______________________________________                                        Compound E-89b'        100 mg                                                 Lactose                60 mg                                                  Potato starch          30 mg                                                  Polyvinyl alcohol      2 mg                                                   Magnesium stearate     1 mg                                                   Tar pigment            trace                                                  ______________________________________                                    

PHARMACEUTICAL PREPARATION 2 Powder

Powders having the following composition are prepared in a conventionalmanner.

    ______________________________________                                        Compound E-62b         20 mg                                                  Lactose                300 mg                                                 ______________________________________                                    

PHARMACEUTICAL PREPARATION 3 Syrup

Syrup having the following composition is prepared in a conventionalmanner.

    ______________________________________                                        Compound E-41b'         100 mg                                                Refined sugar           30 mg                                                 Ethyl p-hydroxybenzoate 40 mg                                                 Propyl p-hydroxybenzoate                                                                              10 mg                                                 Strawberry flavor       0.1 cc                                                ______________________________________                                    

Water is added to make the whole volume 100 cc.

PHARMACEUTICAL PREPARATION 4 Capsule

Capsule having the following composition is prepared in a conventionalmanner.

    ______________________________________                                        Compound E-62b         20 mg                                                  Lactose                200 mg                                                 Magnesium stearate     5 mg                                                   ______________________________________                                    

The composition was mixed and packed in a gelatin capsule.

PHARMACEUTICAL PREPARATION 5 Injection

Injection having the following composition is prepared in a conventionalmanner.

    ______________________________________                                        Compound E-62b         20 mg                                                  Sodium chloride        45 mg                                                  ______________________________________                                    

Water for injection was added to the composition to make the wholevolume 5 ml (amount per 1 ampoule). The solution was distilled andsterilized ina n autoclave.

What is claimed is:
 1. A tricyclic compound represented by formula (I):##STR231## wherein: represent(a) single bond or (b) double bond; X¹ --X²represents:(a) --CH₂ --O--, (b) --CH₂ --S--, (c) --CH₂ --CH₂ -- and (d)--CH═CH--; each of G_(A) and G^(B) independently represents:(a) loweralkyl, (b) halogen and (c) OR¹ wherein R¹ represents: (a) ' hydrogen and(b) ' lower alkyl; each of g^(A) and g^(B) independently represents 0,1, 2 or 3; one of R^(A) and R^(B) represents(a) hydrogen and the otherrepresents(b) --Y--COOR^(1a) wherein R^(1a) has the same significancefor R¹ as described above, Y represents:(a) ' single bond (b) '--CR^(1b)R^(1c) --(CH₂)_(a) -- and (c) '--CR^(1b) ═CR^(1c) --(CH₂)₁ -- whereineach of R^(1b) and R^(1c) independently has the same significances forR¹ as described above and, m represent 0, 1, 2, 3 or 4, wherein the leftside of the formula in (b)' and (c)' is bound to the mother nucleus; W¹represents:(a) --S--, (b) --SO₂ 13 , (c) --O--, (d) --NR^(1d) whereinR^(1d) has the same significance for R¹ as described above, (e)--NHCO--, (f) ═N--, (g) ═CH-- and (h) --Ch₂ --; wherein the left side ofthe formula in (e) through (g) is bound to the mother nucleus; nrepresents 0, 1, 2, 3 or 4; W² represents:(a) single bond, (b) -S- band(c) --NR^(1c) wherein R^(1c) has the same significance for R¹ asdescribed above; Z represents: ##STR232## wherein each of A¹, a², a³ anda⁴ independently represents:(a) '--CH₂ --, (b) '--NH--, (c) '--O--, (d)'--S-- and (e) '--SO₂ --; each of Q¹, Q² and Q³ independentlyrepresents: (a) ' hydrogen(b) ' lower alkyl, (c) ' benzyl, (d) 'substituted benzyl wherein each substituent on the phenyl in thesubstituted benzyl independently represents 1 to 3 groups which are: (a)" halogen and (b) " OR^(1f) wherein R^(1f) has the same significance forR¹ as described above; and, a substituent on the methylene represents(c)" --OR^(1g) wherein R^(1g) has the same significance for R¹ as describedabove; (e) ' phenyl, (f) ' halogen, (g) ' --CF₃, (h) ' nitro (i) ' --CN,(j) ' --N₃, (k) ' --COOR², (l) ' --OR², (m) ' --OCOR², (n) '--SR² (o)'--COR² (p) '--CONR^(2a) R^(2b), wherein each of R^(2a) and R^(2b)independently represents R², wherein R² represents:(a) " hydrogen (b) "straight or branched alkyl having 1 to 18 carbon atoms, (c) " benzyl and(d) " phenyl; (q) ' methylenedioxy formed together with theortho-position; on the saturated carbon atoms (methylene) of (e) and (h)in the definition for Z, (r) '=O and, (s) '=S;and pharmaceuticallyacceptable salts thereof.
 2. A compound according to claim 1, whereinone of R^(A) and R^(B) represents hydrogen and the other represents--Y--COOH.
 3. A compound according to claim 2, wherein Y is a memberselected from the group consisting of single bond, --CH₂ --, ##STR233##and --CH₂ CH₂ --.
 4. A compound according to claim 3, wherein X¹ --X²represents --CH₂ --O--, W¹ represents ═CH--, n is 1 and W² representssingle bond.
 5. A compound according to claim 3, wherein X¹ --X²represents --CH₂ --O--; W¹ represents --S--, --O--, ∇N--, or ═CH--; n is1 or 2; and W² represents single bond. 6.11-[2-[(1,2,3,4-Tetrahydroisoquinolin)-2-yl]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-methylcarboxylate. 7.1-[2-[(1,2,3,4-Tetrahydroisoquinolin-2-yl]ethyl]thio-6,11-dihydrodibenz[b,e] oxepin-2-carboxylic acid. 8.11-[2-[6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolin)-2-yl]ethyl]thio-6,11-dihydrodibenz[b,e] oxepin-2-methyl carboxylate. 9.11-[2-[6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolin)-2-yl]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid. 10.11-[3-[1,2,3,4-Tetrahydroisoquinolin-2-yl]propylidene]-6,11-dihydrodibenz[b,e] oxepin-2-methyl carboxylate. 11.11-[3-[1,2,3,4-Tetrahydroisoquinolin-2-yl]propylidene]-6,11-dihydrodibenz[b,e] oxepin-2-carboxylic acid.
 12. A compound according to claim 1,wherein said salt is selected from the group consisting of acid additionsalt, metal salt, ammonium salt, organic amine addition salt and aminoacid addition salt.
 13. A pharmaceutical composition comprising apharmaceutical carrier and, as an active ingredient, an effective amountof tricyclic compound as defined by claim 1.